bims-mecami 2023-07-30 papers

Issue of 2023–07–30
five papers selected by
Oltea Sampetrean, Keio University

Trends Cancer. 2023 Jul 26. pii: S2405-8033(23)00125-5. [Epub ahead of print]

Sphingolipid metabolism and complement signaling in cancer progression.

Alhaji H Janneh, Carl Atkinson, Stephen Tomlinson, Besim Ogretmen.

Cancer treatment options are limited due to therapeutic resistance; thus, understanding the tumor microenvironment (TME) is crucial. Sphingolipid metabolism and complement activation products have essential roles in promoting tumor survival. Emerging evidence shows that sphingolipid signaling can regulate intracellular complement activation to induce inflammasome-mediated metastasis, offering a promising strategy for cancer therapy.

Keywords: S1P receptor signaling; complement signaling; sphingolipid metabolism; sphingosine 1-phosphate (S1P)

DOI: https://doi.org/10.1016/j.trecan.2023.07.001

Mol Cancer. 2023 Jul 24. 22(1): 118

Molecular and metabolic regulation of immunosuppression in metastatic pancreatic ductal adenocarcinoma.

Shailendra K Gautam, Surinder K Batra, Maneesh Jain.

Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival. Compared to the localized tumors, current standard-of-care therapies have failed to improve the survival of patients with metastatic PDAC, that necessecitates exploration of novel therapeutic approaches. While immunotherapies such as immune checkpoint blockade (ICB) and therapeutic vaccines have emerged as promising treatment modalities in certain cancers, limited responses have been achieved in PDAC. Therefore, specific mechanisms regulating the poor response to immunotherapy must be explored. The immunosuppressive microenvironment driven by oncogenic mutations, tumor secretome, non-coding RNAs, and tumor microbiome persists throughout PDAC progression, allowing neoplastic cells to grow locally and metastasize distantly. The metastatic cells escaping the host immune surveillance are unique in molecular, immunological, and metabolic characteristics. Following chemokine and exosomal guidance, these cells metastasize to the organ-specific pre-metastatic niches (PMNs) constituted by local resident cells, stromal fibroblasts, and suppressive immune cells, such as the metastasis-associated macrophages, neutrophils, and myeloid-derived suppressor cells. The metastatic immune microenvironment differs from primary tumors in stromal and immune cell composition, functionality, and metabolism. Thus far, multiple molecular and metabolic pathways, distinct from primary tumors, have been identified that dampen immune effector functions, confounding the immunotherapy response in metastatic PDAC. This review describes major immunoregulatory pathways that contribute to the metastatic progression and limit immunotherapy outcomes in PDAC. Overall, we highlight the therapeutic vulnerabilities attributable to immunosuppressive factors and discuss whether targeting these molecular and immunological "hot spots" could improve the outcomes of PDAC immunotherapies.

Keywords: Exosomes; Immune and metabolic checkpoints; Immunosuppression; Microbiome; Non-coding RNA; Pre-metastatic niche

DOI: https://doi.org/10.1186/s12943-023-01813-y

Cell Metab. 2023 Jul 21. pii: S1550-4131(23)00251-6. [Epub ahead of print]

Tumor aerobic glycolysis confers immune evasion through modulating sensitivity to T cell-mediated bystander killing via TNF-α.

Lijian Wu, Yiteng Jin, Xi Zhao, Kaiyang Tang, Yaoning Zhao, Linjie Tong, Xuerong Yu, Ke Xiong, Ce Luo, Jiajun Zhu, Fubing Wang, Zexian Zeng, Deng Pan.

Metabolic reprogramming toward glycolysis is a hallmark of cancer malignancy. The molecular mechanisms by which the tumor glycolysis pathway promotes immune evasion remain to be elucidated. Here, by performing genome-wide CRISPR screens in murine tumor cells co-cultured with cytotoxic T cells (CTLs), we identified that deficiency of two important glycolysis enzymes, Glut1 (glucose transporter 1) and Gpi1 (glucose-6-phosphate isomerase 1), resulted in enhanced killing of tumor cells by CTLs. Mechanistically, Glut1 inactivation causes metabolic rewiring toward oxidative phosphorylation, which generates an excessive amount of reactive oxygen species (ROS). Accumulated ROS potentiate tumor cell death mediated by tumor necrosis factor alpha (TNF-α) in a caspase-8- and Fadd-dependent manner. Genetic and pharmacological inactivation of Glut1 sensitizes tumors to anti-tumor immunity and synergizes with anti-PD-1 therapy through the TNF-α pathway. The mechanistic interplay between tumor-intrinsic glycolysis and TNF-α-induced killing provides new therapeutic strategies to enhance anti-tumor immunity.

Keywords: T cell-mediated killing; TNF-α; glycolysis; immune evasion

DOI: https://doi.org/10.1016/j.cmet.2023.07.001

Front Immunol. 2023 ;14 1194931

Gut colonization with an obesity-associated enteropathogenic microbe modulates the premetastatic niches to promote breast cancer lung and liver metastasis.

Sheetal Parida, Sumit Siddharth, Himavanth R Gatla, Shaoguang Wu, Guannan Wang, Kathleen Gabrielson, Cynthia L Sears, Brian H Ladle, Dipali Sharma.

Introduction: Obesity, an independent risk factor for breast cancer growth and metastatic progression, is also closely intertwined with gut dysbiosis; and both obese state and dysbiosis promote each other. Enteric abundance of Bacteroides fragilis is strongly linked with obesity, and we recently discovered the presence of B. fragilis in malignant breast cancer. Given that enterotoxigenic B. fragilis or ETBF, which secretes B. fragilis toxin (BFT), has been identified as a procarcinogenic microbe in breast cancer, it is necessary to examine its impact on distant metastasis and underlying systemic and localized alterations promoting metastatic progression of breast cancer.
Methods: We used syngeneic mammary intraductal (MIND) model harboring gut colonization with ETBF to query distant metastasis of breast cancer cells. Alterations in the immune network and cytokines/chemokines in the tumor microenvironment and distant metastatic sites were examined using flow cytometry, immunohistochemistry, and multiplex arrays.
Results: ETBF infection initiates a systemic inflammation aiding in the establishment of the premetastatic niche formation in vital organs via increased proinflammatory and protumorigenic cytokines like IL17A, IL17E, IL27p28, IL17A/F, IL6, and IL10 in addition to creating a prometastatic immunosuppressive environment in the liver and lungs rich in myeloid cells, macrophages, and T regulatory cells. It induces remodeling of the tumor microenvironment via immune cell and stroma infiltration, increased vasculogenesis, and an EMT-like response, thereby encouraging early metastatic dissemination ready to colonize the conducive environment in liver and lungs of the breast tumor-bearing mice.
Discussion: In this study, we show that enteric ETBF infection concomitantly induces systemic inflammation, reshapes the tumor immune microenvironment, and creates conducive metastatic niches to potentiate early dissemination and seeding of metastases to liver and lung tissues in agreement with the "seed and soil hypothesis." Our results also support the ETBF-induced "parallel model" of metastasis that advocates for an early dissemination of tumor cells that form metastatic lesions independent of the primary tumor load.

Keywords: B. fragilis; ETBF; breast cancer; immune microenvironment; metastasis

DOI: https://doi.org/10.3389/fimmu.2023.1194931

J Hematol Oncol. 2023 07 25. 16(1): 80

Metabolism, metabolites, and macrophages in cancer.

Mengyuan Li, Yuhan Yang, Liting Xiong, Ping Jiang, Junjie Wang, Chunxiao Li.

Tumour-associated macrophages (TAMs) are crucial components of the tumour microenvironment and play a significant role in tumour development and drug resistance by creating an immunosuppressive microenvironment. Macrophages are essential components of both the innate and adaptive immune systems and contribute to pathogen resistance and the regulation of organism homeostasis. Macrophage function and polarization are closely linked to altered metabolism. Generally, M1 macrophages rely primarily on aerobic glycolysis, whereas M2 macrophages depend on oxidative metabolism. Metabolic studies have revealed that the metabolic signature of TAMs and metabolites in the tumour microenvironment regulate the function and polarization of TAMs. However, the precise effects of metabolic reprogramming on tumours and TAMs remain incompletely understood. In this review, we discuss the impact of metabolic pathways on macrophage function and polarization as well as potential strategies for reprogramming macrophage metabolism in cancer treatment.

Keywords: Cancer; Metabolism; Metabolism reprogramming; Tumour microenvironment; Tumour-associated macrophages

DOI: https://doi.org/10.1186/s13045-023-01478-6