bims-mampoc 2022-02-13 papers

bims-mampoc

Biomed News

on Macrophage metabolism and polarization in cancer

Issue of 2022–02–13
28 papers selected by
Alessandra Castegna, University of Bari “Aldo Moro”

Understanding the impact of chemotherapy on the immune landscape of high-grade serous ovarian cancer.
Phosphoinositide-binding protein TIPE1 promotes alternative activation of macrophages and tumor progression via PIP3/Akt/TGF-β axis.
Ferroptosis, as the most enriched programmed cell death process in glioma, induces immunosuppression and immunotherapy resistance.
Epigenetic Modifications in Tumor-Associated Macrophages: A New Perspective for an Old Foe.
Targeting macrophages for enhancing CD47 blockade-elicited lymphoma clearance and overcoming tumor-induced suppression.
Itaconate and fumarate derivatives inhibit priming and activation of the canonical NLRP3 inflammasome in macrophages.
2-methylpyridine-1-ium-1-sulfonate modifies tumor-derived exosome mediated macrophage polarization: Relevance to the tumor microenvironment.
SENP7 senses oxidative stress to sustain metabolic fitness and antitumor functions of CD8+ T cells.
Leveraging Macrophages for Cancer Theranostics.
TNFSF15 facilitates differentiation and polarization of macrophages toward M1 phenotype to inhibit tumor growth.
The role of exosomal miR-181b in the crosstalk between NSCLC cells and tumor-associated macrophages.
Inflammasome activation and pyroptosis via a lipid-regulated SIRT1-p53-ASC axis in macrophages from male mice and humans.
Cilengitide, an αvβ3-integrin inhibitor, enhances the efficacy of anti-programmed cell death-1 therapy in a murine melanoma model.
cPLA2 blockade attenuates S100A7-mediated breast tumorigenicity by inhibiting the immunosuppressive tumor microenvironment.
PD-L1+CD8+ T cells enrichment in lung cancer exerted regulatory function and tumor-promoting tolerance.
Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity.
Glutamine Metabolism-Regulated Nanoparticles to Enhance Chemoimmunotherapy by Increasing Antigen Presentation Efficiency.
The role of NFATc1/c-myc/PKM2/IL-10 axis in activating cervical cancer tumor-associated M2 macrophage polarization to promote cervical cancer progression.
PD-1 agonism by anti-CD80 inhibits T cell activation and alleviates autoimmunity.
Senescence and the tumor-immune landscape: Implications for cancer immunotherapy.
SLAMF6/Ly108 promotes the development of hepatocellular carcinoma via facilitating macrophage M2 polarization.
Enhanced proton treatment with a LDLR-ligand peptide-conjugated gold nanoparticles targeting the tumor microenvironment in an infiltrative brain tumor model.
Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression.
Tumor-Infiltrating PD-1+ Immune Cell Density is Associated with Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer.
Possible Cytoprotection of Low Dose Lipopolysaccharide in Rat Thioacetamide-Induced Liver Lesions, Focusing on the Analyses of Hepatic Macrophages and Autophagy.
PGC1α/β EXPRESSION PREDICTS THERAPEUTIC RESPONSE TO OXIDATIVE PHOSPHORYLATION INHIBITION IN OVARIAN CANCER.
CX3CR1 Acts as a Protective Biomarker in the Tumor Microenvironment of Colorectal Cancer.
DNA-Damage-Response-Targeting Mitochondria-Activated Multifunctional Prodrug Strategy for Self-defensive Tumor Therapy.

Gynecol Oncol Rep. 2022 Feb;39 100926

Understanding the impact of chemotherapy on the immune landscape of high-grade serous ovarian cancer.

Rami Vanguri, Jamal Benhamida, Jonathan H Young, Yanyun Li, Oliver Zivanovic, Dennis Chi, Alexandra Snyder, Travis J Hollmann, Katherine L Mager.

   Objectives: We quantitatively characterized the change in temporospatial expression of repressive and stimulatory checkpoints across immune cell populations in the tumor microenvironment in a cohort of high grade serous ovarian carcinomas (HGSOC) using matched samples before and after neoadjuvant platinum-based chemotherapy.
Methods: Using retrospectively collected matched tissue samples from 9 patients, cell populations were assessed using multiplex immunofluorescence using the Vectra Multispectral Imaging System (Perkin Elmer). We used multiple panels to assess: tumor (AE1/AE3), T cells (CD3, CD8, FOXP3), macrophages (CD68) as well as immune checkpoints (C3aR, PD-1, PD-L1, LAG3, IDO, ICOS, GITR). IHC staining was performed for folate receptor status. Changes in immune cell populations as well as intensities of associated repressive and stimulatory proteins were assessed pre- to post-treatment.
Results: We observed a consistently high pre-treatment stromal macrophage population which is reduced post-chemotherapy with post-treatment enrichment in macrophage PD-L1 expression. While inhibitory checkpoint expression on T cells was heterogeneous post-chemotherapy, we observed a change in the ThICOS+:Treg ratio which resulted in ThICOS+ cells outnumbering Treg cells post-treatment. Spatial analysis revealed the proximity of Treg cells to ThICOS+ T cells decreased post-treatment. We also observed upward shifts in Teff:Treg T cell ratios with retention of immune checkpoints PD-1, LAG3 and GITR.
Conclusions: In this unique dataset of pre and post matched chemotherapy treated HGSOC patients, we observed changes in immune cell subsets expressing repressive or stimulatory proteins resulting in immune compositions more favorable to checkpoint modulations, suggesting novel therapeutic strategies in the recurrent setting.

Keywords:  Immunotherapy; Ovarian cancer; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.gore.2022.100926
Cancer Res. 2022 Feb 08. pii: canres.0003.2021. [Epub ahead of print]

Phosphoinositide-binding protein TIPE1 promotes alternative activation of macrophages and tumor progression via PIP3/Akt/TGF-β axis.

Yang Cheng, Fuxiang Bai, Xiaolei Ren, Renhui Sun, Xiaowei Guo, Wen Liu, Bo Wang, Yongheng Yang, Xiaolu Zhang, Yong Xu, Chunyang Li, Xiaoyun Yang, Lifen Gao, Chunhong Ma, Xueen Li, Xiaohong Liang.

Macrophages perform key and distinct functions in maintaining tissue homeostasis by finely tuning their activation state. Within the tumor microenvironment, macrophages are reshaped to drive tumor progression. Here we report that tumor necrosis factor α-induced protein 8-like 1 (TIPE1) is highly expressed in macrophages, and that depletion of TIPE1 impedes alternative activation of macrophages. TIPE1 enhanced activation of the PI3K/Akt pathway in macrophages by directly binding with and regulating the metabolism of phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3). Accordingly, inhibition of the PI3K/Akt pathway significantly attenuated the effect of TIPE1 on macrophage alternative activation. Tumor-associated macrophages (TAM) in human liver cancer and melanoma tissues showed significantly upregulated TIPE1 expression that negatively correlated with patient survival. In vitro and in vivo, TIPE1 knockdown in macrophages retarded the growth and metastasis of liver cancer and melanoma. Furthermore, blockade or depletion of TGF-β signaling in macrophages abrogated the effects of TIPE1 on tumor cell growth and migration. Together, these results highlight that the phosphoinositide-related signaling pathway involves reprogramming tumor-associated macrophages to optimize the microenvironment for cancer progression.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-0003
Neuro Oncol. 2022 Feb 11. pii: noac033. [Epub ahead of print]

Ferroptosis, as the most enriched programmed cell death process in glioma, induces immunosuppression and immunotherapy resistance.

Tianqi Liu, Chen Zhu, Xin Chen, Gefei Guan, Cunyi Zou, Shuai Shen, Jianqi Wu, Yuhang Wang, Zhiguo Lin, Ling Chen, Peng Cheng, Wen Cheng, Anhua Wu.

   BACKGROUND: Immunosuppressive microenvironment is a major cause of immunotherapeutic resistance in glioma. In addition to secreting compounds, tumor cells under programmed cell death (PCD) processes release abundant mediators to modify the neighboring microenvironment. However, the complex relationship among PCD status, immunosuppressive microenvironment and immunotherapy is still poorly understood.
METHODS: Four independent glioma cohorts comprising 1,750 patients were enrolled for analysis. The relationships among PCD status, microenvironment cellular components and biological phenotypes were fully explored. Tissues from our hospital and experiments in vitro and in vivo were used to confirm the role of ferroptosis in glioma.
RESULTS: Analyses to determine enriched PCD processes showed that ferroptosis was the main type of PCD in glioma. Enriched ferroptosis correlated with progressive malignancy, poor outcomes and aggravated immunosuppression in glioblastoma (GBM) patients. Enhanced ferroptosis was shown to induce activation and infiltration of immune cells but attenuated antitumor cytotoxic killing. Tumor-associated macrophages (TAMs) were found to participate in ferroptosis-mediated immunosuppression. Preclinically, ferroptosis inhibition combined with PD-1/L1 blockade generated a synergistic therapeutic outcome in GBM murine models.
CONCLUSIONS: This work provides a molecular, clinical and biological landscape of ferroptosis, suggesting a role of ferroptosis in glioma malignancy and a novel synergic immunotherapeutic strategy that combines immune checkpoint blockade (ICB) treatment with ferroptosis inhibition.

Keywords:  ICB; Programmed cell death; ferroptosis; immune microenvironment; immunotherapy

DOI:  https://doi.org/10.1093/neuonc/noac033
Front Immunol. 2022 ;13 836223

Epigenetic Modifications in Tumor-Associated Macrophages: A New Perspective for an Old Foe.

Yuqin Niu, Jianxiang Chen, Yiting Qiao.

  Tumorigenesis is frequently accompanied by chronic inflammation, and the tumor microenvironment (TME) can be considered an ecosystem that consists of tumor cells, endotheliocytes, fibroblasts, immune cells and acellular components such as extracellular matrix. For tumor cells, their survival advantages are dependent on both genetic and epigenetic alterations, while other cells mainly present epigenetic modifications. Macrophages are the most plastic type of immune cells and undergo diverse epigenetic alterations in the TME. Some of these epigenetic modifications mitigate against cancer progression, and others accelerate this process. Due to the complex roles of macrophages in the TME, it is urgent to understand their epigenetic modifications associated with the TME. Here, we mainly summarize recent findings on TME-associated epigenetic alterations of tumor-associated macrophages (TAMs), including DNA methylation, posttranslational modifications of histone proteins, chromatin remodeling, and noncoding RNA-mediated epigenetic regulation. At the end of this review, we also discuss the translational potential of these epigenetic modifications for developing novel cancer therapies targeting TAMs.

Keywords:  acetylation; chromatin remodeling; epigenetic modification; histone modification; lncRNA; methylation; tumor associated macrophage (TAM); tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.836223
Blood. 2022 Feb 08. pii: blood.2021013901. [Epub ahead of print]

Targeting macrophages for enhancing CD47 blockade-elicited lymphoma clearance and overcoming tumor-induced suppression.

Xu Cao, Yingyu Wang, Wencan Zhang, Xiancai Zhong, E Gulsen Gunes, Jessica Dang, Jinhui Wang, Alan L Epstein, Christiane Querfeld, Zuoming Sun, Steven Terry Rosen, Mingye Feng.

Tumor-associated macrophages (TAMs) are often the most abundant immune cells in the tumor microenvironment (TME). Strategies targeting TAMs to enable tumor cell killing through cellular phagocytosis have emerged as promising cancer immunotherapy. While several phagocytosis checkpoints have been identified, the desired efficacy has not yet been achieved by blocking such checkpoints in preclinical models or clinical trials. Here, we showed that late-stage Non-Hodgkin's Lymphoma (NHL) was resistant to therapy targeting phagocytosis checkpoint CD47, due to the compromised capacity of TAMs to phagocytose lymphoma cells. Via a high-throughput screening of FDA-approved anti-cancer small molecule compounds, we identified paclitaxel as a potentiator that promotes the clearance of lymphoma by directly evoking phagocytic capability of macrophages, independently of paclitaxel's chemotherapeutic cytotoxicity toward cancer cells. A combination with paclitaxel dramatically enhanced the anti-cancer efficacy of CD47-targeted therapy toward late-stage NHL. Analysis of TME by single-cell RNA sequencing identified paclitaxel-induced TAM populations with an upregulation of genes for tyrosine kinase signaling. The activation of Src family tyrosine kinases (SFK) signaling in macrophages by paclitaxel promoted phagocytosis against NHL cells. In addition, we identified a role of paclitaxel in modifying the TME by preventing the accumulation of a TAM subpopulation that is only present in late-stage lymphoma resistant to CD47-targeted therapy. Our findings identify a novel and effective strategy for NHL treatment, by remodeling TME to enable the tumoricidal roles of TAMs. Furthermore, we characterize TAM subgroups that determine the efficiency of lymphoma phagocytosis in the TME and can be potential therapeutic targets to unleash the anti-tumor activities of macrophages.

DOI: https://doi.org/10.1182/blood.2021013901
Immunology. 2022 Feb 09.

Itaconate and fumarate derivatives inhibit priming and activation of the canonical NLRP3 inflammasome in macrophages.

Christopher Hoyle, Jack P Green, Stuart M Allan, David Brough, Eloise Lemarchand.

  The NLRP3 inflammasome is a multi-protein complex that regulates caspase-1 activation and subsequent interleukin (IL)-1β and IL-18 release from innate immune cells in response to infection or injury. Derivatives of the metabolites itaconate and fumarate, dimethyl itaconate (DMI), 4-octyl itaconate (4OI) and dimethyl fumarate (DMF), limit both expression and release of IL-1β following NLRP3 inflammasome activation. However, the direct effects of these metabolite derivatives on NLRP3 inflammasome responses require further investigation. Using murine bone marrow-derived macrophages, mixed glia and organotypic hippocampal slice cultures (OHSCs), we demonstrate that DMI, 4OI and DMF pre-treatment inhibit pro-inflammatory cytokine production in response to lipopolysaccharide (LPS), as well as inhibiting subsequent NLRP3 inflammasome activation induced by nigericin. DMI, 4OI, DMF and monomethyl fumarate (MMF), another fumarate derivative, also directly inhibited biochemical markers of NLRP3 activation in LPS-primed macrophages, mixed glia, OHSCs and human macrophages in response to nigericin and imiquimod, including ASC speck formation, caspase-1 activation, gasdermin D cleavage and IL-1β release. DMF, an approved treatment for multiple sclerosis, as well as DMI, 4OI and MMF, inhibited NLRP3 activation in macrophages in response to lysophosphatidylcholine, which is used to induce demyelination, suggesting a possible mechanism for DMF in multiple sclerosis through NLRP3 inhibition. The derivatives also reduced pro-IL-1α cleavage in response to the calcium ionophore ionomycin. Together, these findings reveal the immunometabolic regulation of both the priming and activation steps of NLRP3 activation in macrophages. Furthermore, we highlight itaconate and fumarate derivatives as potential therapeutic options in NLRP3- and IL-1α-driven diseases, including in the brain.

Keywords:  NLRP3; fumarate; inflammasome; interleukin; itaconate

DOI:  https://doi.org/10.1111/imm.13454
Int Immunopharmacol. 2022 Feb 08. pii: S1567-5769(22)00065-0. [Epub ahead of print]106 108581

2-methylpyridine-1-ium-1-sulfonate modifies tumor-derived exosome mediated macrophage polarization: Relevance to the tumor microenvironment.

Mohsen Rastegari-Pouyani, Hamid-Reza Mohammadi-Motlagh, Kaveh Baghaei, Kamran Mansouri, Mahsa Hajivalili, Ali Mostafaie, Davar Amani.

  The compound "2-methylpyridine-1-ium-1-sulfonate" (MPS) is the active constituent of Allium hirtifolium Boiss. bulbs with potent anti-angiogenic and anti-cancer activities. Tumor microenvironment (TME) plays a key role in tumor progression via tumor derived exosome (TEX) mediated polarization of M2 type tumor associated macrophages (TAMs). In this study, we explored direct and colorectal cancer (CRC) exosome-mediated impacts of MPS on macrophage polarization to find out whether MPS could modify TEX in favor of anti-tumor M1-like macrophage polarization. After MPS isolation and characterization, first its direct anti-cancer effects were evaluated on HT-29 cells. Then, TEX were isolated from untreated (C-TEX) and MPS-treated (MPS-TEX) HT-29 cells. THP-1 M0 macrophages were incubated with MPS, C-TEX and MPS-TEX. Macrophage polarization was evaluated by flow cytometry, ELISA and gene expression analysis of several M1- and M2-related markers. MPS induced apoptosis and cell cycle arrest and reduced the migration ability of HT-29 cells. C-TEX polarized M0 macrophages toward a mixed M1-/M2-like phenotype with a high predominance of M2-like cells. Macrophage treatment with MPS was associated with the induction of M1-like phenotype. Also, MPS was demonstrated to ameliorate TEX-mediated effects in favor of M1-like polarization. In conclusion, our study addresses for the first time, the potential capability of MPS in skewing macrophages toward an anti-cancer M1-like phenotype both directly and in a TEX-dependent manner. Thus, in addition to its direct anti-cancer effects, this compound could also modify TME in favor of tumor eradication via its direct and TEX-mediated effects on macrophage polarization as a novel anti-cancer mechanism.

Keywords:  2-methylpyridine-1-ium-1-sulfonate; Colorectal cancer; Tumor associated macrophages; Tumor derived exosomes; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.intimp.2022.108581
J Clin Invest. 2022 Feb 10. pii: e155224. [Epub ahead of print]

SENP7 senses oxidative stress to sustain metabolic fitness and antitumor functions of CD8+ T cells.

Zhongqiu Wu, Haiyan Huang, Qiaoqiao Han, Zhilin Hu, Xiao-Lu Teng, Rui Ding, Youqiong Ye, Xiaoyan Yu, Ren Zhao, Zhengting Wang, Qiang Zou.

  The functional integrity of CD8+ T cells is tightly coupled to metabolic reprogramming, but how oxidative stress directs CD8+ T cell metabolic fitness in the tumor microenvironment (TME) remains elusive. Here, we report that SUMO-specific protease 7 (SENP7) senses oxidative stress to maintain the CD8+ T cell metabolic state and antitumor functions. SENP7-deficient CD8+ T cells exhibited decreased glycolysis and oxidative phosphorylation, resulting in attenuated proliferation in vitro and dampened antitumor functions in vivo. Mechanistically, CD8+ T cell-derived reactive oxygen species (ROS) triggered cytosolic SENP7-mediated PTEN deSUMOylation, thereby promoting PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, lowering T cell-intrinsic ROS restricted SENP7 cytosolic translocation and repressed CD8+ T cell metabolic and functional activity in human colorectal cancer samples. Our findings reveal that SENP7, as an oxidative stress sensor, sustains CD8+ T cell metabolic fitness and effector functions and unveil an oxidative stress-sensing machinery in tumor-infiltrating CD8+ T cells.

Keywords:  Adaptive immunity; Cancer immunotherapy; Immunology; Metabolism; T cells

DOI:  https://doi.org/10.1172/JCI155224
Adv Drug Deliv Rev. 2022 Feb 07. pii: S0169-409X(22)00026-6. [Epub ahead of print] 114136

Leveraging Macrophages for Cancer Theranostics.

Lu Liu, Hongjun Li, Jinqiang Wang, Jinchao Zhang, Xing-Jie Liang, Weisheng Guo, Zhen Gu.

  As fundamental immune cells in innate and adaptive immunity, macrophages engage in a double-edged relationship with cancer. Dissecting the character of macrophages in cancer development facilitates the emergence of macrophages-based new strategies that encompass macrophages as theranostic targets/tools of interest for treating cancer. Herein, we provide a concise overview of the mixed roles of macrophages in cancer pathogenesis and invasion as a foundation for the review discussions. We survey the latest progress on macrophage-based cancer theranostic strategies, emphasizing two major strategies, including targeting the endogenous tumor-associated macrophages (TAMs) and engineering the adoptive macrophages to reverse the immunosuppressive environment and augment the cancer theranostic efficacy. We also discuss and provide insights on the major challenges along with exciting opportunities for the future of macrophage-based cancer theranostic approaches.

Keywords:  cancer theranostics; cell therapy; drug delivery; immunotherapy; macrophage

DOI:  https://doi.org/10.1016/j.addr.2022.114136
Oncoimmunology. 2022 ;11(1): 2032918

TNFSF15 facilitates differentiation and polarization of macrophages toward M1 phenotype to inhibit tumor growth.

Can-Can Zhao, Qiu-Ju Han, Hao-Yan Ying, Xiang-Xiang Gu, Na Yang, Lu-Yuan Li, Qiang-Zhe Zhang.

  Macrophages of the M2 phenotype in malignant tumors significantly aid tumor progression and metastasis, as opposed to the M1 phenotype that exhibits anti-cancer characteristics. Raising the ratio of M1/M2 is thus a promising strategy to ameliorate the tumor immunomicroenvironment toward cancer inhibition. We report here that tumor necrosis factor superfamily-15 (TNFSF15), a cytokine with anti-angiogenic activities, is able to facilitate the differentiation and polarization of macrophages toward M1 phenotype. We found that tumors formed in mice by Lewis lung carcinoma (LLC) cells artificially overexpressing TNFSF15 exhibited retarded growth. The tumors displayed a greater percentage of M1 macrophages than those formed by mock-transfected LLC cells. Treatment of mouse macrophage RAW264.7 cells with recombinant TNFSF15 led to augmentation of the phagocytic and pro-apoptotic capacity of the macrophages against cancer cells. Mechanistically, TNFSF15 activated STAT1/3 in bone marrow cells and MAPK, Akt and STAT1/3 in naive macrophages. Additionally, TNFSF15 activated STAT1/3 but inactivated STAT6 in M2 macrophages. Modulations of these signals gave rise to a reposition of macrophage phenotypes toward M1. The ability of TNFSF15 to promote macrophage differentiation and polarization toward M1 suggests that this unique cytokine may have a utility in the reconstruction of the immunomicroenvironment in favor of tumor suppression.

Keywords:  TNFSF15; cancer immunity; differentiation; macrophage; polarization; tumor microenvironment

DOI:  https://doi.org/10.1080/2162402X.2022.2032918
Genes Genomics. 2022 Feb 12.

The role of exosomal miR-181b in the crosstalk between NSCLC cells and tumor-associated macrophages.

Junliang Ma, Shaolin Chen, Yingjie Liu, Hao Han, Ming Gong, Yongxiang Song.

   BACKGROUND: It has been reported that tumor-associated macrophages (TAMs) participate in modulating the progression of cancer in the tumor microenvironment. However, the crosstalk between TAMs and non-small cell lung cancer (NSCLC) is still unclear.
OBJECTIVE: We investigated whether NSCLC-derived exosomes could affect TAMs, which feedback modulated progression of NSCLC.
METHODS: MiR-181b expression was measured by RT-PCR. Human THP-1 monocyte was differentiated into macrophages with phorbol myristate acetate, which were further identified by transmission electron microscopy and western blot. Macrophage M1 and M2 polarizations were detected by flow cytometry, RT-PCR and western blot. Proliferation, migration, and invasion of NSCLC cells treated with conditioned mediums were detected by EdU and Transwell assays.
RESULTS: We demonstrated that miR-181b was up-regulated in exosomes derived from NSCLC patients' serum and NSCLC cells. MiR-181b could be transferred to macrophages via exosomes in the co-culture system of macrophages and NSCLC cells, which promoted macrophage M2 polarization. Further examinations revealed that exosomes derived from NSCLC cells could enhanced macrophage M2 polarizations by regulating miR-181b/JAK2/STAT3 axis, and silencing miR-181b in NSCLC cells and JAK2 inhibitor used in macrophages could reverse the effects. Importantly, the conditioned medium of macrophages treated with NSCLC cell-derived exosomes could promote NSCLC cell proliferation, migration, and invasion. Silencing miR-181b in NSCLC cells and JAK2 inhibitor used in macrophages could block the effects.
CONCLUSIONS: All of these results indicated that exosomal miR-181b participated in the crosstalk between NSCLC cells and TAMs, providing potential therapeutic targets for NSCLC.

Keywords:  Exosomes; JAK2/STAT3 signaling pathway; MiR-181b; Non-small cell lung cancer (NSCLC); Tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.1007/s13258-022-01227-y
Endocrinology. 2022 Feb 05. pii: bqac014. [Epub ahead of print]

Inflammasome activation and pyroptosis via a lipid-regulated SIRT1-p53-ASC axis in macrophages from male mice and humans.

Yimao Huang, Peter Yong, Deborah Dickey, Setu M Vora, Hao Wu, David A Bernlohr.

  Obesity-linked diabetes is associated with accumulation of pro-inflammatory macrophages into adipose tissue leading to inflammasome activation and pyroptotic secretion of IL-1β and IL-18. Targeting fatty acid binding protein 4 (FABP4) uncouples obesity from inflammation, attenuates characteristics of type II diabetes and is mechanistically linked to the cellular accumulation of monounsaturated fatty acids in macrophages. Herein we show that pharmacologic inhibition or genetic deletion of FABP4 activates SIRT1 and deacetylates its downstream targets p53 and STAT3. Pharmacologic inhibition of fatty acid synthase or stearoyl CoA desaturase inhibits, whereas exogenous addition of C16:1 or C18:1 but not their saturated acyl chain counterparts, activates SIRT1 and p53/STAT3 signaling and IL-1β/IL-18 release. Expression of the p53 target gene ASC required for assembly of the NLRP3 inflammasome is down regulated in FABP4 null mice and macrophage cell lines leading to loss of pro-caspase 1 activation and pyroptosis. Concomitant with loss of ASC expression in FABP4 -/- macrophages, inflammasome activation, gasdermin D processing and functional activation of pyroptosis are all diminished in FABP4 null macrophages but can be rescued by silencing SIRT1 or exogenous expression of ASC. Taken together, these results reveal a novel lipid-regulated pathway linking to SIRT1-p53-ASC signaling and activation of inflammasome action and pyroptosis.

Keywords:  ASC; SIRT1; fatty acid binding protein 4; inflammasome; p53; pyroptosis

DOI:  https://doi.org/10.1210/endocr/bqac014
Bioengineered. 2022 Feb;13(2): 4557-4572

Cilengitide, an αvβ3-integrin inhibitor, enhances the efficacy of anti-programmed cell death-1 therapy in a murine melanoma model.

Xin Pan, Minxiao Yi, Chaofan Liu, Yu Jin, Bo Liu, Guangyuan Hu, Xianglin Yuan.

  Integrins play an important role in multiple stages of tumor progression and metastasis. Previous studies have shown synergistic effects of combined αvβ6-integrin and αvβ8-integrin inhibitors with immunotherapy. However, the role of αvβ3-integrin inhibitor in tumor immunity is still unclear. In this study, we aimed to elucidate the impact of the αvβ3-integrin inhibitor on PD-L1 expression and sensitivity to immune checkpoint blockade in melanoma. We investigated the effects of cilengitide, an αvβ3-integrin inhibitor, on cell viability and apoptosis of melanoma cell lines. And we explored how cilengitide regulated the expression of PD-L1 in melanoma cells in vitro and in vivo, using immunofluorescence, flow cytometry, Western blotting, and immunohistochemistry. A subcutaneous B16 murine melanoma model was utilized to determine whether combining cilengitide with anti-PD1 therapy inhibited tumor growth and positively regulated tumor microenvironment (TME). Our results showed that cilengitide inhibited cell viability and induced apoptosis in B16 and A375 cell lines. Furthermore, cilengitide decreased PD-L1 expression by reducing STAT3 phosphorylation in two melanoma cell lines. Cilengitide also reduced subcutaneous tumor PD-L1 expression in the B16 murine melanoma model. Accordingly, cilengitide positively regulated antitumor immune responses and provided durable therapy when combined with anti-PD1 monoclonal antibody in the murine melanoma model. This combination therapy reduced tumor growth and extended survival. Our study highlights that cilengitide enhances the efficacy of anti-PD1 therapy and produces a stronger antitumor immune response. This combination therefore represents a novel therapeutic regimen that may improve immunotherapy treratment.

Keywords:  Melanoma; PD-1 blockade; cilengitide; immune checkpoint inhibitor; αvβ3-integrin

DOI:  https://doi.org/10.1080/21655979.2022.2029236
J Exp Clin Cancer Res. 2022 Feb 08. 41(1): 54

cPLA2 blockade attenuates S100A7-mediated breast tumorigenicity by inhibiting the immunosuppressive tumor microenvironment.

Sanjay Mishra, Manish Charan, Rajni Kant Shukla, Pranay Agarwal, Swati Misri, Ajeet K Verma, Dinesh K Ahirwar, Jalal Siddiqui, Kirti Kaul, Neety Sahu, Kunj Vyas, Ayush Arpit Garg, Anum Khan, Wayne O Miles, Jonathan W Song, Nidhi Bhutani, Ramesh K Ganju.

   BACKGROUND: Molecular mechanisms underlying inflammation-associated breast tumor growth are poorly studied. S100A7, a pro-inflammatory molecule has been shown to enhance breast cancer growth and metastasis. However, the S100A7-mediated molecular mechanisms in enhancing tumor growth and metastasis are unclear.
METHODS: Human breast cancer tissue and plasma samples were used to analyze the expression of S100A7, cPLA2, and PGE2. S100A7-overexpressing or downregulated human metastatic breast cancer cells were used to evaluate the S100A7-mediated downstream signaling mechanisms. Bi-transgenic mS100a7a15 overexpression, TNBC C3 (1)/Tag transgenic, and humanized patient-derived xenograft mouse models and cPLA2 inhibitor (AACOCF3) were used to investigate the role of S100A7/cPLA2/PGE2 signaling in tumor growth and metastasis. Additionally, CODEX, a highly advanced multiplexed imaging was employed to delineate the effects of S100A7/cPLA2 inhibition on the recruitment of various immune cells.
RESULTS: In this study, we found that S100A7 and cPLA2 are highly expressed and correlate with decreased overall survival in breast cancer patients. Further mechanistic studies revealed that S100A7/RAGE signaling promotes the expression of cPLA2 to mediate its oncogenic effects. Pharmacological inhibition of cPLA2 suppressed S100A7-mediated tumor growth and metastasis in multiple pre-clinical models including transgenic and humanized patient-derived xenograft (PDX) mouse models. The attenuation of cPLA2 signaling reduced S100A7-mediated recruitment of immune-suppressive myeloid cells in the tumor microenvironment (TME). Interestingly, we discovered that the S100A7/cPLA2 axis enhances the immunosuppressive microenvironment by increasing prostaglandin E2 (PGE2). Furthermore, CO-Detection by indEXing (CODEX) imaging-based analyses revealed that cPLA2 inhibition increased the infiltration of activated and proliferating CD4+ and CD8+ T cells in the TME. In addition, CD163+ tumor associated-macrophages were positively associated with S100A7 and cPLA2 expression in malignant breast cancer patients.
CONCLUSIONS: Our study provides new mechanistic insights on the cross-talk between S100A7/cPLA2 in enhancing breast tumor growth and metastasis by generating an immunosuppressive TME that inhibits the infiltration of cytotoxic T cells. Furthermore, our studies indicate that S100A7/cPLA2 could be used as novel prognostic marker and cPLA2 inhibitors as promising drugs against S100A7-overexpressing aggressive breast cancer.

Keywords:  Breast cancer; Metastasis; PGE2; S100A7; Tumor microenvironment; cPLA2

DOI:  https://doi.org/10.1186/s13046-021-02221-0
iScience. 2022 Feb 18. 25(2): 103785

PD-L1+CD8+ T cells enrichment in lung cancer exerted regulatory function and tumor-promoting tolerance.

Yingxia Zheng, Li Han, Zheyi Chen, Yiyang Li, Bingqian Zhou, Rui Hu, Shiyu Chen, Haibo Xiao, Yanhui Ma, Guohua Xie, Junyao Yang, Xianting Ding, Lisong Shen.

  Immunotherapy targeting checkpoint blockade to rescue T cells from exhaustion has become an essential therapeutic strategy in treating cancers. Till now, little is known about the PD-L1 graphic pattern and characteristics in CD8+ T cells. We combined cytometry by time-of-flight (CyTOF) and imaging mass cytometry (IMC) approaches to analyze CD8+ T cells from primary lung cancers and discovered that PD-L1+CD8+ T cells were enriched in tumor lesions, spatially localized with PD-1+CD8+ T cells. Furthermore, PD-L1+CD8+ T cells exerted regulatory functions that inhibited CD8+ T cells proliferation and cytotoxic abilities through the PD-L1/PD-1 axis. Moreover, tumor-derived IL-27 promotes PD-L1+CD8+ T cells development through STAT1/STAT3 signaling. Single-cell RNA sequencing data analysis further clarified PD-L1+CD8+ T cells elevated in the components related to downregulation of adaptive immune response. Collectively, our data demonstrated that PD-L1+CD8+ T cells enriched in lung cancer engaged in tolerogenic effects and may become a therapeutic target in lung cancer.

Keywords:  Biological sciences; Immune system; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2022.103785
Immunity. 2022 Feb 08. pii: S1074-7613(22)00035-8. [Epub ahead of print]55(2): 324-340.e8

Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity.

Kebria Hezaveh, Rahul S Shinde, Andreas Klötgen, Marie Jo Halaby, Sara Lamorte, M Teresa Ciudad, Rene Quevedo, Luke Neufeld, Zhe Qi Liu, Robbie Jin, Barbara T Grünwald, Elisabeth G Foerster, Danica Chaharlangi, Mengdi Guo, Priya Makhijani, Xin Zhang, Trevor J Pugh, Devanand M Pinto, Ileana L Co, Alison P McGuigan, Gun Ho Jang, Rama Khokha, Pamela S Ohashi, Grainne M O'Kane, Steven Gallinger, William W Navarre, Heather Maughan, Dana J Philpott, David G Brooks, Tracy L McGaha.

  The aryl hydrocarbon receptor (AhR) is a sensor of products of tryptophan metabolism and a potent modulator of immunity. Here, we examined the impact of AhR in tumor-associated macrophage (TAM) function in pancreatic ductal adenocarcinoma (PDAC). TAMs exhibited high AhR activity and Ahr-deficient macrophages developed an inflammatory phenotype. Deletion of Ahr in myeloid cells or pharmacologic inhibition of AhR reduced PDAC growth, improved efficacy of immune checkpoint blockade, and increased intra-tumoral frequencies of IFNγ+CD8+ T cells. Macrophage tryptophan metabolism was not required for this effect. Rather, macrophage AhR activity was dependent on Lactobacillus metabolization of dietary tryptophan to indoles. Removal of dietary tryptophan reduced TAM AhR activity and promoted intra-tumoral accumulation of TNFα+IFNγ+CD8+ T cells; provision of dietary indoles blocked this effect. In patients with PDAC, high AHR expression associated with rapid disease progression and mortality, as well as with an immune-suppressive TAM phenotype, suggesting conservation of this regulatory axis in human disease.

Keywords:  T cells; aryl hydrocarbon receptor; immune suppression; immunotherapy; indoles; macrophage; metabolism; microbiome; pancreatic cancer; tumor microenvironment

DOI:  https://doi.org/10.1016/j.immuni.2022.01.006
ACS Appl Mater Interfaces. 2022 Feb 09.

Glutamine Metabolism-Regulated Nanoparticles to Enhance Chemoimmunotherapy by Increasing Antigen Presentation Efficiency.

Bin Du, Qingqing Jiao, Yimeng Bai, Min Yu, Mengxue Pang, Mengmeng Zhao, Huizhen Ma, Hanchun Yao.

  Although the strategies to induce dendritic cells (DCs) maturation and promote their antigen presentation can stimulate the tumor immune response, the endogenous deficiency and immunosuppression of DCs reduce antigen utilization, which limits antigen presentation efficiency and reduces immunotherapy effectiveness. Here, we report an endogenous stimulus-responsive nanodelivery system (DOX@HFn-MSO@PGZL). On the one hand, doxorubicin (DOX) promoted antigen presentation by DCs after the immunogenic death of tumor cells. On the other hand, l-methionine sulfoximine (MSO) regulated the glutamine metabolism of tumor-associated macrophages (TAMs) to induce a shift toward the M1-type. M1-TAMs synergistically presented antigens with mature DCs and were more frequently produced to destroy the tumor suppressive immune microenvironment, resulting in the alleviation of DCs functional inhibition. Ultimately, the antigen presentation efficiency was improved, completely activating tumor immunity and exhibiting powerful antitumor effects.

Keywords:  antigen presentation; chemoimmunotherapy; glutamine metabolism; immune activation; immunogenic cell death

DOI:  https://doi.org/10.1021/acsami.1c21417
Exp Cell Res. 2022 Feb 02. pii: S0014-4827(22)00045-3. [Epub ahead of print] 113052

The role of NFATc1/c-myc/PKM2/IL-10 axis in activating cervical cancer tumor-associated M2 macrophage polarization to promote cervical cancer progression.

Jiahong Tan, Linna Yang, Han Zhao, Ying Ai, Li Ren, Fen Zhang, Wei Dong, Ru Shi, Dawei Sun, Yun Feng.

  Nuclear factor of activated T cells 1 (NFATc1) is mainly expressed in tumor microenvironment, especially in macrophages. However, whether NFATc1 is involved in the polarization of tumor associated macrophages (TAMs) and tumor progression in cervical cancer (CC) remains unclear. Immunofluorescence staining was used to detect the expression of CD68 and NFATc1 in CC tissues or adjacent normal tissues of patients. RT-qPCR, flow cytometry, ELISA, and inhibitors treatment were used to observe the effect of NFATc1 on TAMs polarization. Clonal formation, scratch, and transwell assays were used to examine the effects of NFATc1-transfected macrophages or NFATc1-transfected TAM on tumor proliferation, migration, and invasion. Further, a xenograft model was established to confirm the roles of NFATc1+ TAM in CC tumorigenesis. NFATc1+CD68+/CD68+ TAMs ratio was significantly increased in CC tissues compared with the normal tissue, and NFATc1+ TAM showed an M2-like TAM subtype. NFATc1 induced macrophages to secrete IL-10, which further induced M2 polarization of macrophages. Mechanically, the c-myc-PKM2 pathway mediated the expression of IL-10 in NFATc1-induced macrophages. Functionally, NFATc1 induced M2 macrophages promoted the proliferation, migration, and invasion of CC cells, and the knockout of NFATc1 in TAMs significantly inhibited the tumor-promoting function of TAMs. Further, the tumorigenesis test in nude mice confirmed that NFATc1+ TAM promoted the tumorigenicity of CC cells in vivo. In conclusion, NFATc1 mediated IL-10 secretion by regulating the c-myc/PKM2 pathway, thereby induce M2 polarization of TAMs and promote the progression of CC.

Keywords:  Cervical cancer; IL-10; M2 polarization; NFATc1; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.yexcr.2022.113052
Nat Immunol. 2022 Feb 10.

PD-1 agonism by anti-CD80 inhibits T cell activation and alleviates autoimmunity.

Daisuke Sugiura, Il-Mi Okazaki, Takeo K Maeda, Takumi Maruhashi, Kenji Shimizu, Rieko Arakaki, Tatsuya Takemoto, Naozumi Ishimaru, Taku Okazaki.

Targeted blockade of the checkpoint molecule programmed cell death 1 (PD-1) can activate tumor-specific T cells to destroy tumors, whereas targeted potentiation of PD-1 is expected to suppress autoreactive T cells and alleviate autoimmune diseases. However, the development of methods to potentiate PD-1 remains challenging. Here we succeeded in eliciting PD-1 function by targeting the cis-PD-L1-CD80 duplex, formed by binding of CD80 to the PD-1 ligand PD-L1, that attenuates PD-L1-PD-1 binding and abrogates PD-1 function. By generating anti-CD80 antibodies that detach CD80 from the cis-PD-L1-CD80 duplex and enable PD-L1 to engage PD-1 in the presence of CD80, we demonstrate that the targeted dissociation of cis-PD-L1-CD80 duplex elicits PD-1 function in the condition where PD-1 function is otherwise restricted. We demonstrate using murine models that the removal of PD-1 restriction is effective in alleviating autoimmune disease symptoms. Our findings establish a method to potentiate PD-1 function and propose the removal of restraining mechanisms as an efficient strategy to potentiate the function of inhibitory molecules.

DOI: https://doi.org/10.1038/s41590-021-01125-7
Semin Cancer Biol. 2022 Feb 07. pii: S1044-579X(22)00026-8. [Epub ahead of print]

Senescence and the tumor-immune landscape: Implications for cancer immunotherapy.

Loretah Chibaya, Jarin Snyder, Marcus Ruscetti.

  Cancer therapies, including conventional chemotherapy, radiation, and molecularly targeted agents, can lead to tumor eradication through a variety of mechanisms. In addition to their effects on tumor cell growth and survival, these regimens can also influence the surrounding tumor-immune microenvironment in ways that ultimately impact therapy responses. A unique biological outcome of cancer therapy is induction of cellular senescence. Senescence is a damage-induced stress program that leads to both the durable arrest of tumor cells and remodeling the tumor-immune microenvironment through activation of a collection pleiotropic cytokines, chemokines, growth factors, and proteinases known as the senescence-associated secretory phenotype (SASP). Depending on the cancer context and the mechanism of action of the therapy, the SASP produced following therapy-induced senescence (TIS) can promote anti-tumor immunity that enhances therapeutic efficacy, or alternatively chronic inflammation that leads to therapy failure and tumor relapse. Thus, a deeper understanding of the mechanisms regulating the SASP and components necessary for robust anti-immune surveillance in different cancer and therapy contexts are key to harnessing senescence for tumor control. Here we draw a roadmap to modulate TIS and its immune-stimulating features for cancer immunotherapy.

Keywords:  Cellular senescence; Immunotherapy; Senescence-associated secretory phenotype; Senotherapeutics; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.semcancer.2022.02.005
Oncol Lett. 2022 Mar;23(3): 83

SLAMF6/Ly108 promotes the development of hepatocellular carcinoma via facilitating macrophage M2 polarization.

Qi Meng, Xiuyun Duan, Qingchao Yang, Dewen Xue, Zihao Liu, Yuanyuan Li, Qingyan Jin, Fang Guo, Shijie Jia, Zhaofeng Wang, Wenjiang Yan, Xu Chang, Peng Sun.

  Tumor-associated macrophages (TAMs) are capable of worsening hepatocellular carcinoma (HCC) prognosis by accelerating tumor growth and progression. Signaling lymphocyte activation molecule family member 6 (SLAMF6; Ly108 in mice) is an immune regulator that is involved in numerous diseases. However, whether SLAMF6 might affect macrophage function in HCC has not yet been reported. Therefore, the present study aimed to determine the relationship between SLAMF6 expression on macrophages and HCC progression. In the present study, the expression of SLAMF6 in human blood samples and mice was analyzed by flow cytometry. Furthermore, macrophage-related polarization markers were detected via reverse transcription quantitative PCR. Clonogenic formation and Transwell assay were performed to determine the proliferation, migration and invasion of HCC cells. In addition, a murine HCC model was established to detect the function of SLAMF6 in vivo. The results demonstrated that SLAMF6 expression was increased in CD14+ cells obtained from patients with HCC. It was also determined that this increase was associated with a positive hepatitis B virus DNA status and high levels of α-fetoprotein. Polarized TAMs from THP-1 cells, murine peritoneal macrophages and murine bone marrow-derived macrophages all exhibited higher levels of SLAMF6 compared with M1 cells. Furthermore, an increased expression of Ly108 was detected in macrophages obtained from mice tumor tissues, indicating that the tumor microenvironment may promote Ly108 expression and macrophage M2 polarization. Ly108 small interfering RNA was applied to macrophages, which resulted in the suppression of M2 polarization. Ly108-silenced macrophages attenuated HCC cell migration and invasion and prevented tumor growth by inhibiting the nuclear factor-κB pathway. Altogether, the results from the present study suggested that SLAMF6/Ly108 was upregulated in TAMs, which may in turn accelerate the development of HCC.

Keywords:  M2 macrophage; hepatocellular carcinoma; signaling lymphocyte activation molecule family member 6/Ly108

DOI:  https://doi.org/10.3892/ol.2022.13203
Am J Cancer Res. 2022 ;12(1): 198-209

Enhanced proton treatment with a LDLR-ligand peptide-conjugated gold nanoparticles targeting the tumor microenvironment in an infiltrative brain tumor model.

Seungjun Seo, Eun Ho Kim, Won-Seok Chang, Won-Seok Lee, Ki-Hwan Kim, Jong-Ki Kim.

The tumor microenvironment (TME) of glioblastoma malforms (GBMs) contains tumor invasiveness factors, microvascular proliferation, migratory cancer stem cells and infiltrative tumor cells, which leads to tumor recurrence in the absence of effective drug delivery in a Blood Brain Barrier (BBB)-intact TME and radiological invisibility. Low-density lipoprotein receptor (LDLR) is abundant in the blood brain barrier and overexpressed in malignant glioma cells. This study aimed to treat the TME with transmitted proton sensitization of LDLR ligand-functionalized gold nanoparticles (ApoB@AuNPs) in an infiltrative F98 glioma rat model. BBB-crossing ApoB@AuNPs were selectively taken up in microvascular endothelial cells proliferation and pericyte invasion, which are therapeutic targets in the glioma TME. Proton sensitization treated the TME and bulk tumor volume with enhanced therapeutic efficacy by 67-75% compared to that with protons alone. Immunohistochemistry demonstrated efficient treatment of endothelial cell proliferation and migratory tumor cells of invasive microvessels in the TME with saving normal tissues. Taken together, these data indicate that the use of LDLR ligand-functionalized gold nanoparticles is a promising strategy to treat infiltrative malignant glioma while overcoming BBB crossing.

Keywords: BBB crossing; LDLR-transcytosis; TME targeting gold nanoparticles; Tumor microenvironment; glioblastoma malforme; proton stimulation
Nat Cell Biol. 2022 Feb 10.

Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression.

De Huang, Yan Wang, J Will Thompson, Tao Yin, Peter B Alexander, Diyuan Qin, Poorva Mudgal, Haiyang Wu, Yaosi Liang, Lianmei Tan, Christopher Pan, Lifeng Yuan, Ying Wan, Qi-Jing Li, Xiao-Fan Wang.

Many cancers have an unusual dependence on glutamine. However, most previous studies have focused on the contribution of glutamine to metabolic building blocks and the energy supply. Here, we report that cancer cells with aberrant expression of glutamate decarboxylase 1 (GAD1) rewire glutamine metabolism for the synthesis of γ-aminobutyric acid (GABA)-a prominent neurotransmitter-in non-nervous tissues. An analysis of clinical samples reveals that increased GABA levels predict poor prognosis. Mechanistically, we identify a cancer-intrinsic pathway through which GABA activates the GABAB receptor to inhibit GSK-3β activity, leading to enhanced β-catenin signalling. This GABA-mediated β-catenin activation both stimulates tumour cell proliferation and suppresses CD8+ T cell intratumoural infiltration, such that targeting GAD1 or GABABR in mouse models overcomes resistance to anti-PD-1 immune checkpoint blockade therapy. Our findings uncover a signalling role for tumour-derived GABA beyond its classic function as a neurotransmitter that can be targeted pharmacologically to reverse immunosuppression.

DOI: https://doi.org/10.1038/s41556-021-00820-9
Clin Colorectal Cancer. 2022 Jan 11. pii: S1533-0028(22)00004-4. [Epub ahead of print]

Tumor-Infiltrating PD-1+ Immune Cell Density is Associated with Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer.

Yusuke Kitagawa, Takashi Akiyoshi, Noriko Yamamoto, Toshiki Mukai, Yukiharu Hiyoshi, Tomohiro Yamaguchi, Toshiya Nagasaki, Yosuke Fukunaga, Toru Hirota, Tetsuo Noda, Hiroshi Kawachi.

   BACKGROUND: Elevated tumor-infiltrating T-cell density is associated with favorable outcomes in patients with rectal cancer treated with neoadjuvant chemoradiotherapy (CRT). Here, we evaluated the significance of programmed cell death 1 (PD-1)-positive cells, regulatory T cells, and macrophages in response to CRT and prognosis.
PATIENTS AND METHODS: We assessed CD8+, PD-1+, FOXP3+, CD68+, and CD163+ intratumoral and stromal cell densities by immunohistochemistry using pre-treatment biopsies from 275 patients with rectal cancer treated with neoadjuvant CRT. We determined the impact of these measurements on response to CRT and survival. Response to CRT was determined by tumor regression grade (TRG) of surgical specimens, with good responders defined as TRG3-4.
RESULTS: Intratumoral CD8+ and PD-1+ cell densities were significantly higher in good responders than in poor responders, whereas stromal CD68+ cell density was significantly lower in good responders as compared with poor responders. The multivariable analysis revealed high intratumoral CD8+ and PD-1+ cell densities to be independently associated with good responders (CD8: odds ratio [OR], 2.27; 95% confidence interval [CI], 1.21 - 4.34, P = .010; PD-1: OR, 1.97; 95%CI, 1.03 - 3.84, P = .039), and improved recurrence-free survival (CD8: hazard ratio [HR], 0.56; 95%CI, 0.32 - 0.98, P = .044; PD-1: HR, 0.37; 95%CI, 0.19 - 0.71, P = .002). Only high intratumoral CD8+ cell density was associated with improved overall survival (P = .022).
CONCLUSION: Pre-treatment high intratumoral PD-1+ and CD8+ cell densities were independently associated with good response to CRT and improved recurrence-free survival, with high intratumoral CD8+ cell density additionally associated with improved overall survival. These values may serve as predictive and prognostic biomarkers in rectal cancer.

Keywords:  CD8 expression; Chemoradiotherapy; Immunohistochemistry; PD-1 expression; Rectal cancer

DOI:  https://doi.org/10.1016/j.clcc.2022.01.004
Toxicol Pathol. 2022 Feb 10. 1926233221076758

Possible Cytoprotection of Low Dose Lipopolysaccharide in Rat Thioacetamide-Induced Liver Lesions, Focusing on the Analyses of Hepatic Macrophages and Autophagy.

Munmun Pervin, Mohammad Rabiul Karim, Mizuki Kuramochi, Takeshi Izawa, Mitsuru Kuwamura, Jyoji Yamate.

  Lipopolysaccharide (LPS) may influence hepatic macrophages and autophagy. We evaluated the potential participation of macrophages and autophagosomes in thioacetamide (TAA)-induced rat liver injury under pretreatment of a low dose LPS (0.1 mg/kg BW, intraperitoneally; nonhepatotoxic dose). F344 rats were pretreated with LPS (LPS + TAA) or saline (TAA alone) at 24 hours before TAA injection (100 mg/kg BW, intraperitoneally); rats were examined on Days 0 (controls), 1, 2, and 3 after TAA injection. Data were compared between TAA alone and LPS + TAA rats. LPS pretreatment significantly reduced TAA-induced hepatic lesion (centrilobular necrosis with inflammation) on Days 1 and 2, being reflected by declined hepatic enzyme values and decreased number of apoptotic cells. LC3B-immunoreacting autophagosomes (as cytoplasmic fine granules) were significantly increased on Days 1 and 2 in hepatocytes of LPS + TAA rats. In LPS + TAA rats, hepatic macrophages reacting to CD68, CD163, and MHC class II mainly on Day 2 and mRNA levels of macrophage-related factors (MCP-1, IL-1β, and IL-4) on Day 1 were significantly decreased. Collectively, the low-dose LPS pretreatment might act as cytoprotection against TAA-induced hepatotoxicity through increased autophagosomes and decreased hepatic macrophages, although the dose/time-dependent cytoprotection of LPS should be further investigated at molecular levels.

Keywords:  autophagy; hepatic macrophages; lipopolysaccharide; rat; thioacetamide

DOI:  https://doi.org/10.1177/01926233221076758
Cancer Res. 2022 Feb 07. pii: canres.1223.2021. [Epub ahead of print]

PGC1α/β EXPRESSION PREDICTS THERAPEUTIC RESPONSE TO OXIDATIVE PHOSPHORYLATION INHIBITION IN OVARIAN CANCER.

Carmen Ghilardi, Catarina Moreira Barbosa, Laura Brunelli, Paola Ostano, Nicolò Panini, Monica Lupi, Alessia Anastasia, Fabio Fiordaliso, Monica Salio, Laura Formenti, Massimo Russo, Edoardo Arrigoni, Ferdinando Chiaradonna, Giovanna Chiorino, Giulio F Draetta, Joseph R Marszalek, Christopher P Vellano, Roberta Pastorelli, Maria Rosa Bani, Alessandra Decio, Raffaella Giavazzi.

Ovarian cancer (OC) is the deadliest gynecological cancer, and novel therapeutic options are crucial to improve overall survival. Here we provide evidence that impairment of oxidative phosphorylation (OXPHOS) can help control OC progression, and this benefit correlates with expression of the two mitochondrial master regulators PGC-1α and PGC-1β. In orthotopic patient-derived ovarian cancer xenografts (OC-PDX), concomitant high expression of PGC-1α and PGC-1β (PGC-1α/β) fostered a unique transcriptional signature, leading to increased mitochondrial abundance, enhanced tricarboxylic acid (TCA) cycling, and elevated cellular respiration that ultimately conferred vulnerability to OXPHOS inhibition. Treatment with the respiratory chain complex I inhibitor IACS-010759 caused mitochondrial swelling and ATP depletion that consequently delayed malignant progression and prolonged the lifespan of high-PGC-1α/β-expressing OC-PDX-bearing mice. Conversely, low-PGC-1α/β OC-PDX were not affected by IACS-010759, thus pinpointing a selective anti-tumor effect of OXPHOS inhibition. The clinical relevance of these findings was substantiated by analysis of ovarian cancer patient datasets, which showed that 25% of all cases displayed high PGC-1α/β expression along with an activated mitochondrial gene program. This study endorses the use of OXPHOS inhibitors to manage ovarian cancer and identifies the high expression of both PGC-1α and β as biomarkers to refine the selection of patients likely to benefit most from this therapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-1223
Front Immunol. 2021 ;12 758040

CX3CR1 Acts as a Protective Biomarker in the Tumor Microenvironment of Colorectal Cancer.

Yuanyi Yue, Qiang Zhang, Zhengrong Sun.

  The tumor microenvironment (TME) plays an important role in the pathogenesis of many cancers. We aimed to screen the TME-related hub genes of colorectal adenoma (CRAD) and identify possible prognostic biomarkers. The gene expression profiles and clinical data of 464 CRAD patients in The Cancer Genome Atlas (TCGA) database were downloaded. The Estimation of STromal and Immune cells in MAlignant Tumours using Expression data (ESTIMATE) algorithm was performed to calculate the ImmuneScore, StromalScore, and EstimateScore. Thereafter, differentially expressed genes (DEGs) were screened. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) analysis were performed to explore the roles of DEGs. Furthermore, univariate and multivariate Cox analyses were accomplished to identify independent prognostic factors of CRAD. CX3CR1 was selected as a hub gene, and the expression was confirmed in colorectal cancer (CRC) patients and cell lines. The correlations between CX3CR1 and tumor-infiltrating immune cells were estimated by Tumor IMmune Estimation Resource database (TIMER) and CIBERSORT analysis. Besides, we investigated the effects of coculture with THP-1-derived macrophages with HCT8 cells with low CX3CR1 expression on immune marker expression, cell viability, and migration. There were significant differences in the ImmuneScore and EstimateScore among different stages. Patients with low scores presented significantly lower lifetimes than those in the high-score group. Moreover, we recognized 1,578 intersection genes in ImmuneScore and StromalScore, and these genes were mainly enriched in numerous immune-related biological processes. CX3CR1 was found to be associated with immune cell infiltration levels, immune marker expression, and macrophage polarization. Simultaneous silencing of CX3CR1 and coculture with THP-1 cells further regulated macrophage polarization and promoted the cell proliferation and migration of CRC cells. CX3CR1 was decreased in CRAD tissues and cell lines and was related to T and N stages, tumor differentiation, and prognosis. Our results suggest that CX3CR1 contributes to the recruitment and regulation of immune-infiltrating cells and macrophage polarization in CRC and TAM-induced CRC progression. CX3CR1 may act as a prognostic biomarker in CRC.

Keywords:  CX3CR1; ESTIMATE algorithm; colorectal cancer; immune; prognosis; stromal; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2021.758040
Angew Chem Int Ed Engl. 2022 Feb 08.

DNA-Damage-Response-Targeting Mitochondria-Activated Multifunctional Prodrug Strategy for Self-defensive Tumor Therapy.

Paramesh Jangili, Na Kong, Ji Hyeon Kim, Jun Zhou, Haijun Liu, Xingcai Zhang, Wei Tao, Jong Seung Kim.

  We report a novel multifunctional construct, M1, designed explicitly to target the DNA damage response in cancer cells. M1 contains both a floxuridine (FUDR) and protein phosphatase 2A (PP2A) inhibitor combined with a GSH-sensitive linker. Further conjugation of the triphenylphosphonium moiety allows M1 to undergo specific activation in the mitochondria, where mitochondria-mediated apoptosis is observed. Moreover, M1 has enormous effects on genomic DNA ascribed to FUDR's primary function of impeding DNA/RNA synthesis combined with diminishing PP2A-activated DNA repair pathways. Importantly, mechanistic studies highlight the PP2A obtrusion in FUDR/5-fluorouracil (5-FU) therapy and underscore the importance of its inhibition to harbor therapeutic potential. HCT116 cell xenograft-bearing mice that have a low response rate to 5-FU show a prominent effect with M1, emphasizing the importance of DNA damage response targeting strategies using tumor-specific microenvironment-activatable systems.

Keywords:  DNA damage response; DNA repair; drug delivery; floxuridine; protein phosphatase 2A

DOI:  https://doi.org/10.1002/anie.202117075