bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–10–06
thirty-two papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Immunoediting Dynamics in Glioblastoma: Implications for Immunotherapy Approaches.
  2. Therapeutic targets of armored chimeric antigen receptor T cells navigating the tumor microenvironment.
  3. Senescent neutrophils: a hidden role in cancer progression.
  4. Natural plant-derived polysaccharides targeting macrophage polarization: a promising strategy for cancer immunotherapy.
  5. HSP90 promotes tumor associated macrophage differentiation during triple-negative breast cancer progression.
  6. Tumor microenvironment as a complex milieu driving cancer progression: a mini review.
  7. The metabolic crosstalk of cancer-associated fibroblasts and tumor cells: Recent advances and future perspectives.
  8. Thymosin α1 reverses oncolytic adenovirus-induced M2 polarization of macrophages to improve antitumor immunity and therapeutic efficacy.
  9. Mimicking and analyzing the tumor microenvironment.
  10. Inflammation and Immunity in Liver Neoplasms: Implications for Future Therapeutic Strategies.
  11. Targeting the lung tumor stroma: harnessing nanoparticles for effective therapeutic interventions.
  12. The tumor microenvironment's gambit: Exosomal pawns on the board of head and neck cancer.
  13. The NF-κB1/p50 Subunit Influences the Notch/IL-6-Driven Expansion of Myeloid-Derived Suppressor Cells in Murine T-Cell Acute Lymphoblastic Leukemia.
  14. Air bag-embedded MIL-101(Fe) metal-organic frameworks for an amplified tumor microenvironment activation loop through strategic delivery of iron ions and lentinan.
  15. From pathogenesis to treatment: the impact of bacteria on cancer.
  16. Identifying metabolic limitations in the tumor microenvironment.
  17. Cholesterol metabolism: a positive target to revoke the function of exhausted CAR-NK cells in tumor microenvironment.
  18. Bacteria displaying cytokines heat up the tumor microenvironment.
  19. Remembering Hypoxia: Uncovering the Long-Term Effects of Transient Oxygen Deprivation on IFN Signaling and Progression of Breast Cancer.
  20. Dual activity of Minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment.
  21. Syngeneic Mouse Models for Pre-Clinical Evaluation of CAR T Cells.
  22. CAR-redirected natural killer T cells demonstrate superior antitumor activity to CAR-T cells through multimodal CD1d-dependent mechanisms.
  23. The role and mechanism of compressive stress in tumor.
  24. Impaired mitochondrial oxidative phosphorylation induces CD8+ T cell exhaustion.
  25. Glutamine availability regulates cDC subsets in tissue.
  26. Tumor hypoxia unveiled: insights into microenvironment, detection tools and emerging therapies.
  27. The Adenosinergic Pathway in Non-Small Cell Lung Cancer.
  28. Harnessing brain-body communication to understand cancer.
  29. Dendritic Cell-Targeted Nanoparticles Enhance T Cell Activation and Antitumor Immune Responses by Boosting Antigen Presentation and Blocking PD-L1 Pathways.
  30. Revolutionizing Cancer Treatment: Recent Advances in Immunotherapy.
  31. Decreased Expression of CD247 and CD4 Immune Marker Predicts Poor Prognosis in Triple Negative Breast Cancer.
  32. Proximity-dependent labeling identifies dendritic cells that drive the tumor-specific CD4+ T cell response.
  1. Cancer Control. 2024 Jan-Dec;31:31 10732748241290067
    Immunoediting Dynamics in Glioblastoma: Implications for Immunotherapy Approaches.
    Tasbir Amin, Amana Hossain, Nusrat Jerin, Imteaz Mahmud, Md Ahasanur Rahman, S M Rafiqul Islam, S M Bakhtiar Ul Islam.
      Glioblastoma is an aggressive primary brain tumor that poses many therapeutic difficulties because of the high rate of proliferation, genetic variability, and its immunosuppressive microenvironment. The theory of cancer immunoediting, which includes the phases of elimination, equilibrium, and escape, offers a paradigm for comprehending interactions between the immune system and glioblastoma. Immunoediting indicates the process by which immune cells initially suppress tumor development, but thereafter select for immune-resistant versions leading to tumor escape and progression. The tumor microenvironment (TME) in glioblastoma is particularly immunosuppressive, with regulatory T cells and myeloid-derived suppressor cells being involved in immune escape. To achieve an efficient immunotherapy for glioblastoma, it is crucial to understand these mechanisms within the TME. Existing immunotherapeutic modalities such as chimeric antigen receptor T cells and immune checkpoint inhibitors have been met with some level of resistance because of the heterogeneous nature of the immune response to glioblastoma. Solving these issues is critical to develop novel strategies capable of modulating the TME and re-establishing normal immune monitoring. Further studies should be conducted to identify the molecular and cellular events that underlie the immunosuppressive tumor microenvironment in glioblastoma. Comprehending and modifying the stages of immunoediting in glioblastoma could facilitate the development of more potent and long-lasting therapies.
    Keywords:  chimeric antigen receptor-T; glioblastoma; immunoediting; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1177/10732748241290067
  2. Exp Hematol Oncol. 2024 Sep 30. 13(1): 96
    Therapeutic targets of armored chimeric antigen receptor T cells navigating the tumor microenvironment.
    Xianjun Li, Tianjun Chen, Xuehan Li, Hanyu Zhang, Yingjing Li, Shuyuan Zhang, Shengnan Luo, Tongsen Zheng.
      Chimeric antigen receptor (CAR) T cell therapy, which targets tumors with high specificity through the recognition of particular antigens, has emerged as one of the most rapidly advancing modalities in immunotherapy, demonstrating substantial success against hematological malignancies. However, previous generations of CAR-T cell therapy encountered numerous challenges in treating solid tumors, such as the lack of suitable targets, high immunosuppression, suboptimal persistence, and insufficient infiltration owing to the complexities of the tumor microenvironment, all of which limited their efficacy. In this review, we focus on the current therapeutic targets of fourth-generation CAR-T cells, also known as armored CAR-T cells, and explore the mechanisms by which these engineered cells navigate the tumor microenvironment by targeting its various components. Enhancing CAR-T cells with these therapeutic targets holds promise for improving their effectiveness against solid tumors, thus achieving substantial clinical value and advancing the field of CAR-T cell therapy. Additionally, we discuss potential strategies to overcome existing challenges and highlight novel targets that could further enhance the efficacy of CAR-T cell therapy in treating solid tumors.
    Keywords:  Cancer immunotherapy; Chimeric antigen receptor (CAR) T cell; Solid tumor; T cell engineering; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s40164-024-00564-w
  3. Trends Cell Biol. 2024 Oct 02. pii: S0962-8924(24)00187-9. [Epub ahead of print]
    Senescent neutrophils: a hidden role in cancer progression.
    Ryan N Rys, Arianna Calcinotto.
      Neutrophils have recently received increased attention in cancer because they contribute to all stages of cancer. Neutrophils are so far considered to have a short half-life. However, a growing body of literature has shown that tumor-associated neutrophils (TANs) acquire a prolonged lifespan. This review discusses recent work surrounding the mechanisms by which neutrophils can persist in the tumor microenvironment (TME). It also highlights different scenarios for therapeutic targeting of protumorigenic neutrophils, supporting the idea that, in tumors, inhibition of neutrophil recruitment is not sufficient because these cells can persist and remain hidden from current interventions. Hence, the elimination of long-lived neutrophils should be pursued to increase the efficacy of standard therapy.
    Keywords:  cancer; neutrophils; senescence; senolytic therapy
    DOI:  https://doi.org/10.1016/j.tcb.2024.09.001
  4. Front Immunol. 2024 ;15 1408377
    Natural plant-derived polysaccharides targeting macrophage polarization: a promising strategy for cancer immunotherapy.
    Jingyang Wei, Yanpeng Dai, Ni Zhang, Zijian Wang, Xinchen Tian, Tinghao Yan, Xiaohan Jin, Shulong Jiang.
      Tumor associated macrophages (TAMs) are the predominant innate immune cells in the tumor microenvironment (TME). Cytokines induce the differentiation of macrophages into distinct types of TAMs, primarily characterized by two phenotypes: M1-polarized and M2-polarized. Cancer growth is suppressed by M1-polarized macrophages and promoted by M2-polarized macrophages. The regulation of macrophage M1 polarization has emerged as a promising strategy for cancer immunotherapy. Polysaccharides are important bioactive substances found in numerous plants, manifesting a wide range of noteworthy biological actions, such as immunomodulation, anti-tumor effects, antioxidant capabilities, and antiviral functions. In recent years, there has been a significant increase in interest regarding the immunomodulatory and anti-tumor properties of polysaccharides derived from plants. The regulatory impact of polysaccharides on the immune system is mainly associated with the natural immune response, especially with the regulation of macrophages. This review provides a thorough analysis of the regulatory effects and mechanisms of plant polysaccharides on TAMs. Additionally, an analysis of potential opportunities for clinical translation of plant polysaccharides as immune adjuvants is presented. These insights have greatly advanced the research of plant polysaccharides for immunotherapy in tumor-related applications.
    Keywords:  anticancer immunotherapy; macrophage; polarization; polysaccharide; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1408377
  5. Sci Rep. 2024 09 29. 14(1): 22541
    HSP90 promotes tumor associated macrophage differentiation during triple-negative breast cancer progression.
    Lingjia Hong, Manami Tanaka, Masato Yasui, Mariko Hara-Chikuma.
      Tumor-associated macrophages (TAMs) originating from monocytes are crucial for cancer progression; however, the mechanism of TAM differentiation is unclear. We investigated factors involved in the differentiation of monocytes into TAMs within the tumor microenvironment of triple-negative breast cancer (TNBC). We screened 172 compounds and found that a heat shock protein 90 (HSP90) inhibitor blocked TNBC-induced monocyte-to-TAM differentiation in human monocytes THP-1. TNBC-derived conditional medium (CM) activated cell signaling pathways, including MAP kinase, AKT and STAT3, and increased the expression of TAM-related genes and proteins. These inductions were suppressed by HSP90 inhibition or by knockdown of HSP90 in TNBC. Additionally, we confirmed that TNBC secreted HSP90 extracellularly and that HSP90 itself promoted TAM differentiation. In a mouse tumor model, treatment with an HSP90 inhibitor suppressed tumor growth and reduced TAMs in the tumor microenvironment. Our findings demonstrate the role of HSP90 in TAM differentiation, suggesting HSP90 as a potential target for TNBC immunotherapy due to its regulatory role in monocyte-to-TAM differentiation.
    DOI:  https://doi.org/10.1038/s41598-024-73394-9
  6. Clin Transl Oncol. 2024 Sep 28.
    Tumor microenvironment as a complex milieu driving cancer progression: a mini review.
    Zhengrui Li, Jing Li, Xiaolei Bai, Xufeng Huang, Qi Wang.
      It has been spotlighted that the Tumor Microenvironment (TME) is crucial for comprehending cancer progression and therapeutic resistance. Therefore, this comprehensive review elucidates the intricate architecture of the TME, which encompasses tumor cells, immune components, support cells, and a myriad of bioactive molecules. These constituents collectively foster dynamic interactions that underpin tumor growth, metastasis, and nuanced responses to anticancer therapies. Notably, the TME's role extends beyond mere physical support, serving as a critical mediator in cancer-cell evolution, immune modulation, and treatment outcomes. Innovations targeting the TME, including strategies focused on the vasculature, immune checkpoints, and T-cell therapies, have forged new pathways for clinical intervention. However, the heterogeneity and complexity of the TME present significant challenges, necessitating deeper exploration of its components and their interplay to enhance therapeutic efficacy. This review underscores the imperative for integrated research strategies that amalgamate insights from tumor biology, immunology, and systems biology. Such an approach aims to refine cancer treatments and improve patient prognoses by exploiting the TME's complexity.
    Keywords:  Angiogenesis; Bioactive molecules; Cancer progression; Cellular interactions; Heterogeneity; Immune modulation; Therapeutic resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12094-024-03697-w
  7. Biochim Biophys Acta Rev Cancer. 2024 Sep 26. pii: S0304-419X(24)00121-5. [Epub ahead of print]1879(6): 189190
    The metabolic crosstalk of cancer-associated fibroblasts and tumor cells: Recent advances and future perspectives.
    Bing Xia, Liqing Qiu, Jing Yue, Jingxing Si, Hongfang Zhang.
      Tumor cells grow in a microenvironment with a lack of nutrients and oxygen. Cancer-associated fibroblasts (CAFs) as one major component of tumor microenvironment have strong ability to survive under stressful conditions through metabolic remodelling. Furthermore, CAFs are educated by tumor cells and help them adapt to the hostile microenvironment through their metabolic communication. By inducing catabolism, CAFs release nutrients into the microenvironment which are taken up by tumor cells to satisfy their metabolic requirements. Furthermore, CAFs can recycle toxic metabolic wastes produced by cancer cells into energetic substances, allowing cancer cells to undergo biosynthesis. Their metabolic crosstalk also enhances CAFs' pro-tumor phenotype and reshape the microenvironment facilitating tumor cells' metastasis and immune escape. In this review, we have analyzed the effect and mechanisms of metabolic crosstalk between tumor cells and CAFs. We also analyzed the future perspectives in this area from the points of CAFs heterogeneity, spatial metabonomics and patient-derived tumor organoids (PDOs). These information may deepen the knowledge of tumor metabolism regulated by CAFs and provide novel insights into the development of metabolism-based anti-cancer strategies.
    Keywords:  Anti-cancer strategies; CAFs; Environmental stress; Metabolic crosstalk; Tumor-promoting roles
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189190
  8. Cell Rep Med. 2024 Sep 23. pii: S2666-3791(24)00481-6. [Epub ahead of print] 101751
    Thymosin α1 reverses oncolytic adenovirus-induced M2 polarization of macrophages to improve antitumor immunity and therapeutic efficacy.
    Kua Liu, Lingkai Kong, Huawei Cui, Louqian Zhang, Qilei Xin, Yan Zhuang, Ciliang Guo, Yongzhong Yao, Jinqiu Tao, Xiaosong Gu, Chunping Jiang, Junhua Wu.
      Although oncolytic adenoviruses are widely studied for their direct oncolytic activity and immunomodulatory role in cancer immunotherapy, the immunosuppressive feedback loop induced by oncolytic adenoviruses remains to be studied. Here, we demonstrate that type V adenovirus (ADV) induces the polarization of tumor-associated macrophages (TAMs) to the M2 phenotype and increases the infiltration of regulatory T cells (Tregs) in the tumor microenvironment (TME). By selectively compensating for these deficiencies, thymosin alpha 1 (Tα1) reprograms "M2-like" TAMs toward an antitumoral phenotype, thereby reprogramming the TME into a state more beneficial for antitumor immunity. Moreover, ADVTα1 is constructed by harnessing the merits of all the components for the aforementioned combinatorial therapy. Both exogenously supplied and adenovirus-produced Tα1 orchestrate TAM reprogramming and enhance the antitumor efficacy of ADV via CD8+ T cells, showing promising prospects for clinical translation. Our findings provide inspiration for improving oncolytic adenovirus combination therapy and designing oncolytic engineered adenoviruses.
    Keywords:  M1 polarization; M2 polarization; TAM; TAM reprogramming; Tregs; oncolytic adenovirus; oncolytic virus; regulatory T cells; thymosin α1; tumor associated macrophages; tumor immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101751
  9. Cell Rep Methods. 2024 Sep 25. pii: S2667-2375(24)00244-3. [Epub ahead of print] 100866
    Mimicking and analyzing the tumor microenvironment.
    Roxane Crouigneau, Yan-Fang Li, Jamie Auxillos, Eliana Goncalves-Alves, Rodolphe Marie, Albin Sandelin, Stine Falsig Pedersen.
      The tumor microenvironment (TME) is increasingly appreciated to play a decisive role in cancer development and response to therapy in all solid tumors. Hypoxia, acidosis, high interstitial pressure, nutrient-poor conditions, and high cellular heterogeneity of the TME arise from interactions between cancer cells and their environment. These properties, in turn, play key roles in the aggressiveness and therapy resistance of the disease, through complex reciprocal interactions between the cancer cell genotype and phenotype, and the physicochemical and cellular environment. Understanding this complexity requires the combination of sophisticated cancer models and high-resolution analysis tools. Models must allow both control and analysis of cellular and acellular TME properties, and analyses must be able to capture the complexity at high depth and spatial resolution. Here, we review the advantages and limitations of key models and methods in order to guide further TME research and outline future challenges.
    Keywords:  CP: Biotechnology; CP: Cancer biology; cancer; heterogeneity; metabolism; microfluidics; organoids; tumor microenvironment; tumor models
    DOI:  https://doi.org/10.1016/j.crmeth.2024.100866
  10. Mol Cancer Ther. 2024 Oct 04.
    Inflammation and Immunity in Liver Neoplasms: Implications for Future Therapeutic Strategies.
    Jieun Kim, Ekihiro Seki.
      Over the past two decades, the "hallmarks of cancer" have revolutionized cancer research and highlighted the crucial roles of inflammation and immunity. Pro-tumorigenic inflammation promotes cancer development along with inhibition of anti-tumor immunity, shaping the tumor microenvironment (TME) towards a tumor-permissive state and further enhancing the malignant potential of cancer cells. This immunosuppressive TME allows tumors to evade immunosurveillance. Thus, understanding the complex interplay between tumors and the immune system within the TME has become pivotal, especially with the advent of immunotherapy. Although immunotherapy has achieved notable success in many malignancies, primary liver cancer, particularly hepatocellular carcinoma (HCC), presents unique challenges. The hepatic immunosuppressive environment poses obstacles to the effectiveness of immunotherapy, along with high mortality rates and limited treatment options for patients with liver cancer. In this review, we discuss current understanding of the complex immune-mediated mechanisms underlying liver neoplasms, focusing on HCC and liver metastases. We describe the molecular and cellular heterogeneity within the TME, highlighting how this presents unique challenges and opportunities for immunotherapy in liver cancers. By unraveling the immune landscape of liver neoplasms, this review aims to contribute to the development of more effective therapeutic interventions, ultimately improving clinical outcomes for patients with liver cancer.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-23-0726
  11. J Drug Target. 2024 Oct 02. 1-48
    Targeting the lung tumor stroma: harnessing nanoparticles for effective therapeutic interventions.
    Shushu Zhang, Hui Wang.
      Lung cancer remains an influential global health concern, necessitating the development of innovative therapeutic strategies. The tumor stroma, which is known as tumor microenvironment (TME) has a central impact on tumor expansion and treatment resistance. The stroma of lung tumors consists of numerous cells and molecules that shape an environment for tumor expansion. This environment not only protects tumoral cells against immune system attacks but also enables tumor stroma to attenuate the action of antitumor drugs. This stroma consists of stromal cells like cancer-associated fibroblasts (CAFs), suppressive immune cells, and cytotoxic immune cells. Additionally, the presence of stem cells, endothelial cells and pericytes can facilitate tumor volume expansion. Nanoparticles are hopeful tools for targeted drug delivery because of their extraordinary properties and their capacity to devastate biological obstacles. This review article provides a comprehensive overview of contemporary advancements in targeting the lung tumor stroma using nanoparticles. Various nanoparticle-based approaches, including passive and active targeting, and stimuli-responsive systems, highlighting their potential to improve drug delivery efficiency. Additionally, the role of nanotechnology in modulating the tumor stroma by targeting key components such as immune cells, extracellular matrix (ECM), hypoxia, and suppressive elements in the lung tumor stroma.
    Keywords:  Antitumor Immunity; Lung Cancer; Nanoparticles; Tumor Microenvironment; Tumor Stroma
    DOI:  https://doi.org/10.1080/1061186X.2024.2410462
  12. Biochim Biophys Acta Rev Cancer. 2024 Sep 27. pii: S0304-419X(24)00120-3. [Epub ahead of print]1879(6): 189189
    The tumor microenvironment's gambit: Exosomal pawns on the board of head and neck cancer.
    Solmaz Mohamadi, Parisa Mehrasa, Bahareh Mehramuz, Sepehr Kobravi, Mohammad Taghizadieh, Arash Salmaninejad, Mobina Bayat, Javid Sadri Nahand.
      The tumor microenvironment (TME) harbors a hidden universe of interactions that profoundly shape the behavior of head and neck cancers (HNCs). HNCs are not merely localized afflictions; they constitute a pressing global health crisis that impacts millions, frequently resulting in severe prognoses due to late-stage diagnosis and intrinsic resistance to conventional therapies. In this intricate interplay, cancer cells function as strategic players, adeptly manipulating their microenvironment to foster proliferation, evade immune detection, and withstand therapeutic interventions. Central to this dynamic play are exosomes, the enigmatic pawns of cellular communication, carrying vital messages across the board. This review elucidates the multifaceted roles of exosomes within the TME, highlighting their capacity to transmit critical signals that not only promote tumor progression but also modulate immune responses, ultimately playing a crucial role in the evolving narrative of HNC. Our insights aim to catalyze further research and exploration into exosome-targeted therapies, potentially transforming the landscape of HNC treatment and improving clinical outcomes in this formidable battle against cancer.
    Keywords:  Cancer progression; Exosome; Head and neck cancers; Intercellular communication; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189189
  13. Int J Mol Sci. 2024 Sep 13. pii: 9882. [Epub ahead of print]25(18):
    The NF-κB1/p50 Subunit Influences the Notch/IL-6-Driven Expansion of Myeloid-Derived Suppressor Cells in Murine T-Cell Acute Lymphoblastic Leukemia.
    Behnaz Abdollahzadeh, Noemi Martina Cantale Aeo, Nike Giordano, Andrea Orlando, Maria Basciani, Giovanna Peruzzi, Paola Grazioli, Isabella Screpanti, Maria Pia Felli, Antonio Francesco Campese.
      T-cell acute lymphoblastic leukemia is an aggressive neoplasia due to hyper-proliferation of lymphoid progenitors and lacking a definitive cure to date. Notch-activating mutations are the most common in driving disease onset and progression, often in combination with sustained activity of NF-κB. Myeloid-derived suppressor cells represent a mixed population of immature progenitors exerting suppression of anti-cancer immune responses in the tumor microenvironment of many malignancies. We recently reported that in a transgenic murine model of Notch3-dependent T-cell acute lymphoblastic leukemia there is an accumulation of myeloid-derived suppressor cells, dependent on both Notch signaling deregulation and IL-6 production inside tumor T-cells. However, possible interaction between NF-κB and Notch in this context remains unexplored. Interestingly, we also reported that Notch3 transgenic and NF-κB1/p50 deleted double mutant mice display massive myeloproliferation. Here, we demonstrated that the absence of the p50 subunit in these mice dramatically enhances the induction and suppressive function of myeloid-derived suppressor cells. This runs in parallel with an impressive increase in IL-6 concentration in the peripheral blood serum, depending on IL-6 hyper-production by tumor T-cells from double mutant mice. Mechanistically, IL-6 increase relies on loss of the negative control exerted by the p50 subunit on the IL-6 promoter. Our results reveal the Notch/NF-κB cross-talk in regulating myeloid-derived suppressor cell biology in T-cell leukemia, highlighting the need to consider carefully the pleiotropic effects of NF-κB-based therapy on the tumor microenvironment.
    Keywords:  IL-6; MDSC; NF-κB1/p50; Notch; T-ALL; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms25189882
  14. Theranostics. 2024 ;14(15): 5883-5902
    Air bag-embedded MIL-101(Fe) metal-organic frameworks for an amplified tumor microenvironment activation loop through strategic delivery of iron ions and lentinan.
    Tao Han, Yan Sun, Xi Jiang, Chengming Gong, Fei Kong, Yi Luo, Chang Ge, Congyan Liu, Yuping Liu, Yanfei Mou, Huangqin Zhang, Jianming Ju, Yan Chen, Ding Qu.
      Background: Iron-based nanocarriers have demonstrated potential in redirecting tumor associated macrophages (TAMs) polarization towards the M1 phenotype, critical for activating the tumor microenvironment (TME) in triple negative breast cancer (TNBC). However, their real-world effectiveness is curtailed by insufficient Fe2+/3+ exposure and the absence of suitable synergists in tumors. Methods: We introduce an air bag-embedded iron-based MIL-101 metal-organic frameworks (MOFMIL-101(Fe)) for igniting the TME in TNBC through bubble-driven tumoral codelivery of Fe2+/3+ and lentinan. This system, named HM/Ef/LNT-MOFMIL-101(Fe), features nano-sized MOFMIL-101(Fe) as the core, embedded NaHCO3 as a pH-triggered air bag, electrostatically-adsorbed lentinan forming the inner shell, and a shield shell with 4T1&red blood cell hybrid membrane. Results: HM/Ef/LNT-MOFMIL-101(Fe) can mitigate non-specific capture in the bloodstream but respond to the acidic tumor milieu, rapidly generating a burst of CO2 bubbles to disassemble MOFMIL-101(Fe). Upon entering tumors, lentinan-induced interferon-γ (IFN-γ) enable Fe2+/3+ facilitating an enhanced ferroptosis and Fenton-like reaction, pushing TAMs towards M1 polarization via the "IFN-γ-ferroptosis-ROS-Caspase-3" pathway. Moreover, HM/Ef/LNT-MOFMIL-101(Fe) increases the infiltration of T lymphocytes and decreases regulatory T cells. These cascading immune responses synergistically foster a loop of amplified TME activation based on TAMs M1 polarization, showcasing notable advancements in anticancer effectiveness and promise for various combination therapies. Conclusion: This study utilizes an "embedded air-bag" strategy to achieve strategic codelivery of Fe2+/3+ and lentinan, providing a new tool for engineering the TME.
    Keywords:  Metal-organic frameworks; Polysaccharides; Triple-negative breast cancer; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.7150/thno.99303
  15. Front Microbiol. 2024 ;15 1462749
    From pathogenesis to treatment: the impact of bacteria on cancer.
    Jiatong Lu, Qiang Tong.
      The intricate relationship between cancer and bacteria has garnered increasing attention in recent years. While traditional cancer research has primarily focused on tumor cells and genetic mutations, emerging evidence highlights the significant role of microbial communities within the tumor microenvironment in cancer development and progression. This review aims to provide a comprehensive overview of the current understanding of the complex interplay between cancer and bacteria. We explore the diverse ways in which bacteria influence tumorigenesis and tumor behavior, discussing direct interactions between bacteria and tumor cells, their impact on tumor immunity, and the potential modulation of the tumor microenvironment. Additionally, we delve into the mechanisms through which bacterial metabolites and extracellular products May affect cancer pathways. By conducting a thorough analysis of the existing literature, we underscore the multifaceted and intricate relationship between bacteria and cancer. Understanding this complex interplay could pave the way for novel therapeutic approaches and preventive strategies in cancer treatment.
    Keywords:  bacteria; cancer; therapeutic strategies; tumor prediction; tumorigenesis
    DOI:  https://doi.org/10.3389/fmicb.2024.1462749
  16. Sci Adv. 2024 Oct 04. 10(40): eadq7305
    Identifying metabolic limitations in the tumor microenvironment.
    Guillaume Cognet, Alexander Muir.
      Solid tumors are characterized by dysfunctional vasculature that limits perfusion and delivery of nutrients to the tumor microenvironment. Limited perfusion coupled with the high metabolic demand of growing tumors has led to the hypothesis that many tumors experience metabolic stress driven by limited availability of nutrients such as glucose, oxygen, and amino acids in the tumor. Such metabolic stress has important implications for the biology of cells in the microenvironment, affecting both disease progression and response to therapies. Recently, techniques have been developed to identify limiting nutrients and resulting metabolic stresses in solid tumors. These techniques have greatly expanded our understanding of the metabolic limitations in tumors. This review will discuss these experimental tools and the emerging picture of metabolic limitations in tumors arising from recent studies using these approaches.
    DOI:  https://doi.org/10.1126/sciadv.adq7305
  17. Front Pharmacol. 2024 ;15 1440869
    Cholesterol metabolism: a positive target to revoke the function of exhausted CAR-NK cells in tumor microenvironment.
    Jingfeng Liu.
      
    Keywords:  CAR (chimeric antigen receptor); NK cell; cholesterol; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2024.1440869
  18. Nat Biotechnol. 2024 Oct 04.
    Bacteria displaying cytokines heat up the tumor microenvironment.
    Marine Fidelle, Laurence Zitvogel.
      
    DOI:  https://doi.org/10.1038/s41587-024-02429-3
  19. Cancer Res. 2024 Oct 01. 84(19): 3125-3127
    Remembering Hypoxia: Uncovering the Long-Term Effects of Transient Oxygen Deprivation on IFN Signaling and Progression of Breast Cancer.
    Stephen Connor Purdy, Heide L Ford.
      Hypoxia occurs in 90% of solid tumors and is strongly associated with an increased propensity for metastasis. Hypoxia induces tumor progression largely through inducing HIF-mediated transcription, resulting in alterations to tumor cell metabolism, as well as increases in migration and invasion. Hypoxia also results in a myriad of changes to the tumor microenvironment (TME). While many studies have examined the immediate effects of hypoxia on tumor cells and the associated TME, far fewer have focused on the long-term consequences of transient reductions in oxygen. In this issue of Cancer Research, Iriondo and colleagues examined whether short-term exposure to hypoxia leads to a "hypoxic memory" in the context of breast cancer. The authors used established cell lines and circulating tumor cell lines to demonstrate that these cells harbor a hypoxic memory that sustains downregulation of IFN signaling and antigen presentation (AP) pathways that contribute to tumor progression via alterations to tumor cells and the TME. The authors further showed that cells that have experienced hypoxia maintain the reduction in IFN signaling in vivo and are more aggressive. They determined that the hypoxic memory and reduction of IFN signaling can be reversed with a histone deacetylase inhibitor, entinostat, providing a potential means to reverse hypoxia-induced suppression of IFN signaling. As suppression of IFN signaling has the potential to influence both tumor cells and the TME, the identification of a strategy to inhibit long-term suppression of IFN signaling downstream of hypoxia could prove to be an effective means to target tumor progression. See related article by Iriondo et al., p. 3141.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-2407
  20. Sci Rep. 2024 09 28. 14(1): 22487
    Dual activity of Minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment.
    Fulya Koksalar Alkan, Ahmet Burak Caglayan, Hilmi Kaan Alkan, Elayne Benson, Yunus Emre Gunduz, Ozge Sensoy, Serdar Durdagi, Elbrus Zarbaliyev, Greg Dyson, Hadeel Assad, Austin Shull, Ahmed Chadli, Huidong Shi, Gurkan Ozturk, Hasan Korkaya.
      Triple negative breast cancer (TNBC) subtype is characterized with higher EMT/stemness properties and immune suppressive tumor microenvironment (TME). Women with advanced TNBC exhibit aggressive disease and have limited treatment options. Although immune suppressive TME is implicated in driving aggressive properties of basal/TNBC subtype and therapy resistance, effectively targeting it remains a challenge. Minnelide, a prodrug of triptolide currently being tested in clinical trials, has shown anti-tumorigenic activity in multiple malignancies via targeting super enhancers, Myc and anti-apoptotic pathways such as HSP70. Distinct super-enhancer landscape drives cancer stem cells (CSC) in TNBC subtype while inducing immune suppressive TME. We show that Minnelide selectively targets CSCs in human and murine TNBC cell lines compared to cell lines of luminal subtype by targeting Myc and HSP70. Minnelide in combination with cyclophosphamide significantly reduces the tumor growth and eliminates metastasis by reprogramming the tumor microenvironment and enhancing cytotoxic T cell infiltration in 4T1 tumor-bearing mice. Resection of residual tumors following the combination treatment leads to complete eradication of disseminated tumor cells as all mice are free of local and distant recurrences. All control mice showed recurrences within 3 weeks of post-resection while single Minnelide treatment delayed recurrence and one mouse was free of tumor. We provide evidence that Minnelide targets tumor intrinsic pathways and reprograms the immune suppressive microenvironment. Our studies also suggest that Minnelide in combination with cyclophosphamide may lead to durable responses in patients with basal/TNBC subtype warranting its clinical investigation.
    DOI:  https://doi.org/10.1038/s41598-024-72989-6
  21. Cancers (Basel). 2024 Sep 18. pii: 3186. [Epub ahead of print]16(18):
    Syngeneic Mouse Models for Pre-Clinical Evaluation of CAR T Cells.
    Eman N Ahmed, Lauren C Cutmore, John F Marshall.
      Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of hematological malignancies. Unfortunately, this improvement has yet to be translated into the solid tumor field. Current immunodeficient models used in pre-clinical testing often overestimate the efficacy of CAR T cell therapy as they fail to recapitulate the immunosuppressive tumor microenvironment characteristic of solid tumors. As CAR T cell monotherapy is unlikely to be curative for many solid tumors, combination therapies must be investigated, for example, stromal remodeling agents and immunomodulators. The evaluation of these combination therapies requires a fully immunocompetent mouse model in order to recapitulate the interaction between the host's immune system and the CAR T cells. This review will discuss the need for improved immunocompetent murine models for the pre-clinical evaluation of CAR T cells, the current use of such models and future directions.
    Keywords:  CAR T cells; adoptive cellular therapy; combination therapy; immunotherapy; solid tumors; syngeneic models
    DOI:  https://doi.org/10.3390/cancers16183186
  22. Nat Cancer. 2024 Oct 01.
    CAR-redirected natural killer T cells demonstrate superior antitumor activity to CAR-T cells through multimodal CD1d-dependent mechanisms.
    Xin Zhou, Ying Wang, Zhangqi Dou, Gloria Delfanti, Ourania Tsahouridis, Caroline Marnata Pellegry, Manuela Zingarelli, Gatphan Atassi, Mark G Woodcock, Giulia Casorati, Paolo Dellabona, William Y Kim, Linjie Guo, Barbara Savoldo, Ageliki Tsagaratou, J Justin Milner, Leonid S Metelitsa, Gianpietro Dotti.
      Human natural killer T (NKT) cells have been proposed as a promising cell platform for chimeric antigen receptor (CAR) therapy in solid tumors. Here we generated murine CAR-NKT cells and compared them with CAR-T cells in immune-competent mice. Both CAR-NKT cells and CAR-T cells showed similar antitumor effects in vitro, but CAR-NKT cells showed superior antitumor activity in vivo via CD1d-dependent immune responses in the tumor microenvironment. Specifically, we show that CAR-NKT cells eliminate CD1d-expressing M2-like macrophages. In addition, CAR-NKT cells promote epitope spreading and activation of endogenous T cell responses against tumor-associated neoantigens. Finally, we observed that CAR-NKT cells can co-express PD1 and TIM3 and show an exhaustion phenotype in a model of high tumor burden. PD1 blockade as well as vaccination augmented the antitumor activity of CAR-NKT cells. In summary, our results demonstrate the multimodal function of CAR-NKT cells in solid tumors, further supporting the rationale for developing CAR-NKT therapies in the clinic.
    DOI:  https://doi.org/10.1038/s43018-024-00830-0
  23. Front Oncol. 2024 ;14 1459313
    The role and mechanism of compressive stress in tumor.
    Min Tan, Bingqi Song, Xinbin Zhao, Jing Du.
      Recent research has revealed the important role of mechanical forces in the initiation and progression of tumors. The interplay between mechanical and biochemical cues affects the function and behavior of tumor cells during the development of solid tumors, especially their metastatic potential. The compression force generated by excessive cell proliferation and the tumor microenvironment widely regulates the progression of solid tumor disease. Tumor cells can sense alterations in compressive stress through diverse mechanosensitive components and adapt their mechanical characteristics accordingly to adapt to environmental changes. Here, we summarize the current role of compressive stress in regulating tumor behavior and its biophysical mechanism from the mechanobiological direction.
    Keywords:  cell extrusion; compressive stress; mechanical force; metastasis; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2024.1459313
  24. Biochem Biophys Res Commun. 2024 Sep 24. pii: S0006-291X(24)01274-9. [Epub ahead of print]734 150738
    Impaired mitochondrial oxidative phosphorylation induces CD8+ T cell exhaustion.
    Min Liu, Xinyue Fu, Qinghe Yi, Enhong Xu, Longbao Dong.
      CD8+ T cells play a crucial role in anti-tumor immunity, but their function can be impaired by exhaustion induced by prolonged antigen stimulation. Mitochondrial dysfunction, a hallmark of the tumor microenvironment (TME), has been linked to various pathologies, but its specific role in CD8+ T cell exhaustion remains underexplored. Here, we established an in vitro model of CD8+ T cell exhaustion by co-culturing OVA-specific OT1 CD8+ T cells with OVA-expressing MC38 tumor cells. Next, we investigated the impact of mitochondrial dysfunction on exhaustion using pharmacological inhibitors targeting the electron transport chain. The role of the mitochondrial complex I component NDUFA10 was further examined through genetic knockout in CD8+ T cells using CRISPR-Cas9. Inhibition of the mitochondrial electron transport chain significantly accelerated CD8+ T cell exhaustion in vitro. Knockout of NDUFA10 in CD8+ T cells led to enhanced tumor growth and increased exhaustion of tumor-infiltrating CD8+ T cells in a Rag1-/- tumor-bearing transfer model. This study highlights the critical role of mitochondrial function in regulating CD8+ T cell exhaustion and anti-tumor activity, providing new insights into the metabolic underpinnings of immune dysfunction in cancer.
    Keywords:  CD8(+) T cell; Exhaustion; Mitochondrion
    DOI:  https://doi.org/10.1016/j.bbrc.2024.150738
  25. bioRxiv. 2024 Sep 21. pii: 2024.09.17.613574. [Epub ahead of print]
    Glutamine availability regulates cDC subsets in tissue.
    Graham P Lobel, Nanumi Han, William A Molina Arocho, Michal Silber, Jason Shoush, Michael C Noji, Tsun Ki Jerrick To, Li Zhai, Nicholas P Lesner, M Celeste Simon, Malay Haldar.
      Proliferating tumor cells take up glutamine for anabolic processes engendering glutamine deficiency in the tumor microenvironment. How this might impact immune cells is not well understood. Using multiple mouse models of soft tissue sarcomas, glutamine antagonists, as well as genetic and pharmacological inhibition of glutamine utilization, we found that the number and frequency of conventional dendritic cells (cDC) is dependent on microenvironmental glutamine levels. cDCs comprise two distinct subsets - cDC1 and cDC2, with the former subset playing a critical role in antigen cross-presentation and tumor immunity. While both subsets show dependence on Glutamine, cDC1s are particularly sensitive. Notably, glutamine antagonism did not reduce the frequency of DC precursors but decreased proliferation and survival of cDC1s. Further studies suggest a role of the nutrient sensing mTOR signaling pathway in this process. Taken together, these findings uncover glutamine dependence of cDC1s that is coopted by tumors to escape immune responses.
    One Sentence Summary: Type 1 conventional dendritic cells require glutamine to maintain their number in non-lymphoid tissue.
    Significance: Immune evasion is a key hallmark of cancer; however, the underlying pathways are diverse, tumor-specific and not fully elucidated. Many tumor cells avidly import glutamine to support their anabolic needs, creating a glutamine-deficient tumor microenvironment (TME). Herein, using mouse models of soft tissue sarcomas, we show that glutamine depletion in TME leads to reduced type 1 conventional dendritic cells - a cell type that is critical for adaptive immune responses. This work is a paradigm for how tumor cell metabolism can regulate anti-tumor immune responses and will be foundational to future efforts targeting glutamine metabolism for cancer immunotherapy.
    DOI:  https://doi.org/10.1101/2024.09.17.613574
  26. Clin Exp Med. 2024 Oct 03. 24(1): 235
    Tumor hypoxia unveiled: insights into microenvironment, detection tools and emerging therapies.
    Joanna Ciepła, Ryszard Smolarczyk.
      Hypoxia is one of the defining characteristics of the tumor microenvironment (TME) in solid cancers. It has a major impact on the growth and spread of malignant cells as well as their resistance to common treatments like radiation and chemotherapy. Here, we explore the complex functions of hypoxia in the TME and investigate its effects on angiogenesis, immunological evasion, and cancer cell metabolism. For prognostic and therapeutic reasons, hypoxia identification is critical, and recent developments in imaging and molecular methods have enhanced our capacity to precisely locate underoxygenated areas inside tumors. Furthermore, targeted therapies that take advantage of hypoxia provide a potential new direction in the treatment of cancer. Therapeutic approaches that specifically target hypoxic conditions in tumors without causing adverse effects are being led by hypoxia-targeted nanocarriers and hypoxia-activated prodrugs (HAPs). This review provides an extensive overview of this dynamic and clinically significant area of oncology research by synthesizing current knowledge about the mechanisms of hypoxia in cancer, highlighting state-of-the-art detection methodologies, and assessing the potential and efficacy of hypoxia-targeted therapies.
    Keywords:  Anti-cancer therapy; Cancer; Detection; Hypoxia; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10238-024-01501-1
  27. Cancers (Basel). 2024 Sep 13. pii: 3142. [Epub ahead of print]16(18):
    The Adenosinergic Pathway in Non-Small Cell Lung Cancer.
    Olivier Van Kerkhove, Saartje Verfaillie, Brigitte Maes, Kristof Cuppens.
      Immune checkpoint inhibitors (ICIs) targeting PD-(L)1 and CTLA-4 have revolutionized the systemic treatment of non-small cell lung cancer (NSCLC), achieving impressive results. However, long-term clinical benefits are only seen in a minority of patients. Extensive research is being conducted on novel potential immune checkpoints and the mechanisms underlying ICI resistance. The tumor microenvironment (TME) plays a critical role in modulating the immune response and influencing the efficacy of ICIs. The adenosinergic pathway and extracellular adenosine (eADO) are potential targets to improve the response to ICIs in NSCLC patients. First, this review delves into the adenosinergic pathway and the impact of adenosine within the TME. Second, we provide an overview of relevant preclinical and clinical data on molecules targeting this pathway, particularly focusing on NSCLC.
    Keywords:  adenosine; immune checkpoint inhibition; lung cancer
    DOI:  https://doi.org/10.3390/cancers16183142
  28. Genes Dev. 2024 Oct 03.
    Harnessing brain-body communication to understand cancer.
    Erica K Sloan.
      Solid tumors that arise in the body interact with neurons, which influences cancer progression and treatment response. Here, we discuss key questions in the field, including defining the nature of interactions between tumors and neural circuits and defining how neural signals shape the tumor microenvironment. This information will allow us to optimally target neural signaling to improve outcomes for cancer patients.
    Keywords:  brain–body; physiology; symposium
    DOI:  https://doi.org/10.1101/gad.352292.124
  29. ACS Appl Mater Interfaces. 2024 Sep 30.
    Dendritic Cell-Targeted Nanoparticles Enhance T Cell Activation and Antitumor Immune Responses by Boosting Antigen Presentation and Blocking PD-L1 Pathways.
    Prateek Srivastava, Marie Rütter, Gover Antoniraj, Yvonne Ventura, Ayelet David.
      Dendritic cells (DCs) within the tumor microenvironment (TME) have an insufficient capacity to activate T cells through antigen presentation. Furthermore, the programmed cell-death ligand 1 (PD-L1), abundantly expressed on tumor-associated DCs, binds the programmed cell-death 1 (PD-1)-positive T cells and suppresses their immune function. The binding of PD-L1 to CD80 (B7.1) on the same DC via cis-interactions further prevents T cell costimulation through CD28. Here, we present a strategy to simultaneously promote antigen cross-presentation and block the inhibitory interactions of PD-L1 on DCs to amplify T cell-mediated antitumor responses within the TME. Mesoporous silica nanoparticles (MSNPs) were loaded with clotrimazole (CLT) to boost MHC II-mediated antigen presentation by DCs, surface-modified with mannose to target CD206 on DCs, and then decorated with PD-L1 binding peptide (PDL1bp) to block PD-L1-mediated interactions. PDL1bp was cleaved from the mannosylated and CLT-loaded MSNPs (MSNP-MaN/CLT) under conditions simulating the TME and tethered to PD-L1 to reverse CD80 sequestration on DC2.4 cells. The blocking of PD-L1 by PDL1bp-decorated NPs (MSNP-MaN-PDL1bp) increased the cellular interactions between DC2.4 and EL4 T cells and the amount of IL-2 secretion. The MSNP-MaN/CLT were taken up rapidly by DC2.4 cells, promoted MHC II presentation of hen egg lysozyme (HEL), and increased IL-2 production from HEL antigen-primed 3A9 T cells, which was further enhanced by PDL1bp. In vivo investigation revealed that administration of the CLT-loaded and PDL1bp-functionalized MSNPs remarkably inhibited subcutaneous B16-F10 melanoma tumor growth when compared with anti-PD-L1 therapy. MSNP-MaN-PDL1bp/CLT treatment upregulated the levels of effector molecules such as granzyme B and proinflammatory cytokines (IFNγ and INFα) in the tumor tissue, indicating antitumoral T cell responses. This strategy of utilizing nanoparticles to trigger DC activation while promoting T cell stimulation can be used to amplify the antitumor T cell responses and represents a promising alternative to anti-PD-L1 immunotherapy.
    Keywords:  PD-L1; T cells; antigen presentation; antitumor immunity; clotrimazole; dendritic cells; mesoporous silica nanoparticles; tumor microenvironment
    DOI:  https://doi.org/10.1021/acsami.4c12821
  30. Biomedicines. 2024 Sep 23. pii: 2158. [Epub ahead of print]12(9):
    Revolutionizing Cancer Treatment: Recent Advances in Immunotherapy.
    Rose Ghemrawi, Lama Abuamer, Sedra Kremesh, Ghadeer Hussien, Rahaf Ahmed, Walaa Mousa, Ghalia Khoder, Mostafa Khair.
      Cancer immunotherapy has emerged as a transformative approach in oncology, utilizing the body's immune system to specifically target and destroy malignant cells. This review explores the scope and impact of various immunotherapeutic strategies, including monoclonal antibodies, chimeric antigen receptor (CAR)-T cell therapy, checkpoint inhibitors, cytokine therapy, and therapeutic vaccines. Monoclonal antibodies, such as Rituximab and Trastuzumab, have revolutionized treatment paradigms for lymphoma and breast cancer by offering targeted interventions that reduce off-target effects. CAR-T cell therapy presents a potentially curative option for refractory hematologic malignancies, although challenges remain in effectively treating solid tumors. Checkpoint inhibitors have redefined the management of cancers like melanoma and lung cancer; however, managing immune-related adverse events and ensuring durable responses are critical areas of focus. Cytokine therapy continues to play a vital role in modulating the immune response, with advancements in cytokine engineering improving specificity and reducing systemic toxicity. Therapeutic vaccines, particularly mRNA-based vaccines, represent a frontier in personalized cancer treatment, aiming to generate robust, long-lasting immune responses against tumor-specific antigens. Despite these advancements, the field faces significant challenges, including immune resistance, tumor heterogeneity, and the immunosuppressive tumor microenvironment. Future research should address these obstacles through emerging technologies, such as next-generation antibodies, Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-based gene editing, and AI-driven drug discovery. By integrating these novel approaches, cancer immunotherapy holds the promise of offering more durable, less toxic, and highly personalized treatment options, ultimately improving patient outcomes and survival rates.
    Keywords:  CAR-T cell therapy; cancer immunotherapy; cancer vaccines; checkpoint inhibitors; monoclonal antibodies; personalized medicine
    DOI:  https://doi.org/10.3390/biomedicines12092158
  31. Asian Pac J Cancer Prev. 2024 Sep 01. pii: 91311. [Epub ahead of print]25(9): 3187-3197
    Decreased Expression of CD247 and CD4 Immune Marker Predicts Poor Prognosis in Triple Negative Breast Cancer.
    Ankit Pateriya, Rajeev Nema, Anand Kumar Mishra, Ashok Kumar, Ashutosh Shrivastava.
       OBJECTIVE: Triple negative breast cancer (TNBC) is an aggressive from of breast cancer and is associated with poor prognosis. Tumor microenvironment of breast cancer consists of a wide   range of cell types, including tumor-infiltrating lymphocytes (TILs). Accumulating evidence indicate that TILs play a crucial role in cancer progression and resistance to standard chemotherapy.
    METHOD: We used online computational tools to evaluate the prognostic significance of CD247 and CD4 in TNBC.
    RESULTS: TNBC patients with lower expression of CD247 and CD4 have much shorter relapse- free survival and overall survival than the patients with higher expression of these genes. CD247 and CD4 expression show a strong positive correlation with tumor-infiltrating dendritic cells, B-cells, CD4+, CD8+, and neutrophils.
    CONCLUSION: We've concluded that low levels of CD247 and CD4 may stop immune cells from entering the area around the tumor, which stops cancer cells from being killed and gives the patient a bad outlook. These findings suggest that CD247 and CD4 may be useful biomarkers or as a target to understand the progression of TNBC. Our findings also suggest that CD247 and CD4 targeted therapeutics should be explored in detail, and could be a potentially used as atreatment strategy for TNBC.
    Keywords:  Kaplan-Meier; Triple-negative breast cancer; Tumor Microenvironment; breast cancer; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.31557/APJCP.2024.25.9.3187
  32. Sci Immunol. 2024 Oct 04. 9(100): eadq8843
    Proximity-dependent labeling identifies dendritic cells that drive the tumor-specific CD4+ T cell response.
    Aleksey Chudnovskiy, Tiago B R Castro, Sandra Nakandakari-Higa, Ang Cui, Chia-Hao Lin, Moshe Sade-Feldman, Brooke K Phillips, Juhee Pae, Luka Mesin, Juliana Bortolatto, Lawrence D Schweitzer, Giulia Pasqual, Li-Fan Lu, Nir Hacohen, Gabriel D Victora.
      Dendritic cells (DCs) are uniquely capable of transporting tumor antigens to tumor-draining lymph nodes (tdLNs) and interact with effector T cells in the tumor microenvironment (TME) itself, mediating both natural antitumor immunity and the response to checkpoint blockade immunotherapy. Using LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts)-based single-cell transcriptomics, we identified individual DCs capable of presenting antigen to CD4+ T cells in both the tdLN and TME. Our findings revealed that DCs with similar hyperactivated transcriptional phenotypes interact with helper T cells both in tumors and in the tdLN and that checkpoint blockade drugs enhance these interactions. These findings show that a relatively small fraction of DCs is responsible for most of the antigen presentation in the tdLN and TME to both CD4+ and CD8+ tumor-specific T cells and that classical checkpoint blockade enhances CD40-driven DC activation at both sites.
    DOI:  https://doi.org/10.1126/sciimmunol.adq8843
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