Targeting the Senescent Tumor Microenvironment to Sensitize Immunotherapy

Wen Sun

doi:10.54097/te6m0d54

Authors

Wen Sun

DOI:

https://doi.org/10.54097/te6m0d54

Keywords:

Tumor Microenvironment, Cellular Senescence, Immunotherapy Resistance.

Abstract

The tumor microenvironment (TME) plays a pivotal role in cancer progression, metastasis, and therapeutic resistance. Cellular senescence within the TME, characterized by irreversible growth arrest and the senescence-associated secretory phenotype (SASP), profoundly impacts tumor biology and immunotherapy efficacy. The senescent TME promotes tumor growth, invasion, and metastasis through complex interactions between senescent cells, SASP factors, and the extracellular matrix (ECM). Simultaneously, senescence-induced alterations in immune cell function, including T cell exhaustion, macrophage polarization, and impaired natural killer (NK) cell cytotoxicity, contribute to an immunosuppressive niche that hinders immunosurveillance and fosters tumor immune evasion. Mounting evidence suggests that the senescent TME is a critical mediator of resistance to immune checkpoint inhibitors (ICIs). Senescence-associated changes in the TME dampen antitumor immunity by reducing CD8+ T cell infiltration and functionality while promoting the accumulation of immunosuppressive cell populations such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Consequently, strategies targeting the senescent TME have emerged as promising approaches to enhance ICI efficacy. Senolytic agents, SASP inhibitors, and combinatorial therapies aimed at eliminating senescent cells, modulating SASP, and reprogramming the immunosuppressive TME have shown potential in preclinical models to sensitize tumors to immunotherapy. As our understanding of the senescent TME evolves, it is becoming increasingly clear that a multifaceted approach integrating TME-targeted interventions with immunotherapy is necessary to overcome resistance and improve patient outcomes. Future research should focus on elucidating the molecular mechanisms underlying senescence-driven immunotherapy resistance, identifying robust biomarkers to predict treatment response, and developing novel therapeutic strategies that synergize with ICIs. By harnessing the potential of TME-targeted approaches, we can expand the scope and efficacy of cancer immunotherapy, ultimately leading to improved survival and quality of life for cancer patients.

Downloads

Download data is not yet available.

References

[1] Lamba N, Ott P A, Iorgulescu J B. Use of First-Line Immune Checkpoint Inhibitors and Association with Overall Survival Among Patients with Metastatic Melanoma in the Anti-PD-1 Era [J]. JAMA Netw Open, 2022, 5 (8): e2225459.

[2] Zhang C, Zhang C, Wang H. Immune-checkpoint inhibitor resistance in cancer treatment: Current progress and future directions [J]. Cancer Lett, 2023, 562: 216182.

[3] Zhou S, Lu J, Liu S, et al. Role of the tumor microenvironment in malignant melanoma organoids during the development and metastasis of tumors [J]. Front Cell Dev Biol, 2023, 11: 1166916.

[4] Schreier A, Zappasodi R, Serganova I, et al. Facts and Perspectives: Implications of tumor glycolysis on immunotherapy response in triple negative breast cancer [J]. Front Oncol, 2022, 12: 1061789.

[5] Wang L, Du C, Jiang B, et al. Adjusting the dose of traditional drugs combined with immunotherapy: reshaping the immune microenvironment in lung cancer [J]. Front Immunol, 2023, 14: 1256740.

[6] Mirji G, Worth A, Bhat S A, et al. The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer [J]. Sci Immunol, 2022, 7 (75): eabn0704.

[7] Yang S, Jia J, Wang F, et al. Targeting neutrophils: Mechanism and advances in cancer therapy [J]. Clin Transl Med, 2024, 14(3): e1599.

[8] Deng Y, Chen Q, Yang X, et al. Tumor cell senescence-induced macrophage CD73 expression is a critical metabolic immune checkpoint in the aging tumor microenvironment [J]. Theranostics, 2024, 14 (3): 1224 - 40.

[9] D'ambrosio M, Gil J. Reshaping of the tumor microenvironment by cellular senescence: An opportunity for senotherapies [J]. Dev Cell, 2023, 58 (12): 1007 - 21.

[10] Wang S T, Huang S W, Liu K T, et al. Atorvastatin-induced senescence of hepatocellular carcinoma is mediated by downregulation of hTERT through the suppression of the IL-6/STAT3 pathway [J]. Cell Death Discov, 2020, 6: 17.

[11] Shriki A, Lanton T, Sonnenblick A, et al. Multiple Roles of IL6 in Hepatic Injury, Steatosis, and Senescence Aggregate to Suppress Tumorigenesis [J]. Cancer Res, 2021, 81 (18): 4766 - 77.

[12] Daley D, Mani V R, Mohan N, et al. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance [J]. Nat Med, 2017, 23 (5): 556 - 67.

[13] Nobumoto A, Nagahara K, Oomizu S, et al. Galectin-9 suppresses tumor metastasis by blocking adhesion to endothelium and extracellular matrices [J]. Glycobiology, 2008, 18 (9): 735 - 44.

[14] Huang Y, Yang X, Meng Y, et al. The hepatic senescence-associated secretory phenotype promotes hepatocarcinogenesis through Bcl3-dependent activation of macrophages [J]. Cell Biosci, 2021, 11 (1): 173.

[15] Ma Y, Liang Y, Liang N, et al. Identification and functional analysis of senescence-associated secretory phenotype of premature senescent hepatocytes induced by hexavalent chromium [J]. Ecotoxicol Environ Saf, 2021, 211: 111908.

[16] Fane M, Weeraratna A T. How the ageing microenvironment influences tumour progression [J]. Nat Rev Cancer, 2020, 20 (2): 89 - 106.

[17] Harper E I, Weeraratna A T. A Wrinkle in TIME: How Changes in the Aging ECM Drive the Remodeling of the Tumor Immune Microenvironment [J]. Cancer Discov, 2023, 13 (9): 1973 - 81.

[18] Du H, Bartleson J M, Butenko S, et al. Tuning immunity through tissue mechanotransduction [J]. Nat Rev Immunol, 2023, 23 (3): 174 - 88.

[19] Moreau J F, Pradeu T, Grignolio A, et al. The emerging role of ECM crosslinking in T cell mobility as a hallmark of immunosenescence in humans [J]. Ageing Res Rev, 2017, 35: 322 - 35.

[20] Salmon H, Franciszkiewicz K, Damotte D, et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors [J]. J Clin Invest, 2012, 122 (3): 899 - 910.

[21] Cortesi M, Zanoni M, Pirini F, et al. Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight [J]. Int J Mol Sci, 2021, 23 (1).

[22] Sun W, Yuan Y, Chen J, et al. Construction and validation of a novel senescence-related risk score can help predict the prognosis and tumor microenvironment of gastric cancer patients and determine that STK40 can affect the ROS accumulation and proliferation ability of gastric cancer cells [J]. Front Immunol, 2023, 14: 1259231.

[23] Bancaro N, Calì B, Troiani M, et al. Apolipoprotein E induces pathogenic senescent-like myeloid cells in prostate cancer [J]. Cancer Cell, 2023, 41 (3): 602 - 19. e11.

[24] Reynolds L E, Maallin S, Haston S, et al. Effects of senescence on the tumour microenvironment and response to therapy [J]. Febs j, 2024, 291 (11): 2306 - 19.

[25] Wang V, Heffer A, Roztocil E, et al. TNF-α and NF-κB signaling play a critical role in cigarette smoke-induced epithelial-mesenchymal transition of retinal pigment epithelial cells in proliferative vitreoretinopathy [J]. PLoS One, 2022, 17 (9): e0271950.

[26] Ruhland M K, Loza A J, Capietto A H, et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis [J]. Nat Commun, 2016, 7: 11762.

[27] Toso A, Revandkar A, Di Mitri D, et al. Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity [J]. Cell Rep, 2014, 9 (1): 75 - 89.

[28] Takasugi M, Yoshida Y, Hara E, et al. The role of cellular senescence and SASP in tumour microenvironment [J]. Febs j, 2023, 290 (5): 1348 - 61.

[29] Wang X, Liu C, Chen J, et al. Single-cell dissection of remodeled inflammatory ecosystem in primary and metastatic gallbladder carcinoma [J]. Cell Discov, 2022, 8 (1): 101.

[30] Liu H, Zhao H, Sun Y. Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies [J]. Semin Cancer Biol, 2022, 86 (Pt 3): 769 - 81.

[31] Orjalo A V, Bhaumik D, Gengler B K, et al. Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network [J]. Proc Natl Acad Sci U S A, 2009, 106 (40): 17031 - 6.

[32] Hollander L, Guo X, Velazquez H, et al. Renalase Expression by Melanoma and Tumor-Associated Macrophages Promotes Tumor Growth through a STAT3-Mediated Mechanism [J]. Cancer Res, 2016, 76 (13): 3884 - 94.

[33] Newport E, Pedrosa A R, Lees D, et al. Elucidating the role of the kinase activity of endothelial cell focal adhesion kinase in angiocrine signalling and tumour growth [J]. J Pathol, 2022, 256 (2): 235 - 47.

[34] Xiong J, Dong L, Lv Q, et al. Targeting senescence-associated secretory phenotypes to remodel the tumour microenvironment and modulate tumour outcomes [J]. Clin Transl Med, 2024, 14 (9): e1772.

[35] Mikuła-Pietrasik J, Sosińska P, Naumowicz E, et al. Senescent peritoneal mesothelium induces a pro-angiogenic phenotype in ovarian cancer cells in vitro and in a mouse xenograft model in vivo [J]. Clin Exp Metastasis, 2016, 33 (1): 15 - 27.

[36] Guo D, Ma D, Liu P, et al. DNASE1L3 arrests tumor angiogenesis by impairing the senescence-associated secretory phenotype in response to stress [J]. Aging (Albany NY), 2021, 13 (7): 9874 - 99.

[37] Turajlic S, Sottoriva A, Graham T, et al. Resolving genetic heterogeneity in cancer [J]. Nat Rev Genet, 2019, 20 (7): 40 4 - 16.

[38] Wang X, Ma L, Pei X, et al. Comprehensive assessment of cellular senescence in the tumor microenvironment [J]. Brief Bioinform, 2022, 23 (3).

[39] Dhanasekaran R. Deciphering Tumor Heterogeneity in Hepatocellular Carcinoma (HCC)-Multi-Omic and Singulomic Approaches [J]. Semin Liver Dis, 2021, 41 (1): 9 - 18.

[40] Bektas A, Schurman S H, Sen R, et al. Human T cell immunosenescence and inflammation in aging [J]. J Leukoc Biol, 2017, 102 (4): 977 - 88.

[41] Elyahu Y, Hekselman I, Eizenberg-Magar I, et al. Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes [J]. Sci Adv, 2019, 5 (8): eaaw8330.

[42] Salam N, Rane S, Das R, et al. T cell ageing: effects of age on development, survival & function [J]. Indian J Med Res, 2013, 138 (5): 595 - 608.

[43] Dai L, Shen Y. Insights into T-cell dysfunction in Alzheimer's disease [J]. Aging Cell, 2021, 20 (12): e13511.

[44] Callender L A, Carroll E C, Bober E A, et al. Mitochondrial mass governs the extent of human T cell senescence [J]. Aging Cell, 2020, 19 (2): e13067.

[45] Mogilenko D A, Shpynov O, Andhey P S, et al. Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK (+) CD8 (+) T Cells as Conserved Hallmark of Inflammaging [J]. Immunity, 2021, 54 (1): 99 - 115.e12.

[46] Cheng H, Ma K, Zhang L, et al. The tumor microenvironment shapes the molecular characteristics of exhausted CD8 (+) T cells [J]. Cancer Lett, 2021, 506: 55 - 66.

[47] Song Y, Wang B, Song R, et al. T-cell Immunoglobulin and ITIM Domain Contributes to CD8 (+) T-cell Immunosenescence [J]. Aging Cell, 2018, 17 (2).

[48] Hogan K A, Chini C C S, Chini E N. The Multi-faceted Ecto-enzyme CD38: Roles in Immunomodulation, Cancer, Aging, and Metabolic Diseases [J]. Front Immunol, 2019, 10: 1187.

[49] Dimitrijević M, Stanojević S, Vujić V, et al. Aging oppositely affects TNF-α and IL-10 production by macrophages from different rat strains [J]. Biogerontology, 2014, 15 (5): 475 - 86.

[50] Zhao Q, Hu W, Xu J, et al. Comprehensive Pan-Cancer Analysis of Senescence with Cancer Prognosis and Immunotherapy [J]. Front Mol Biosci, 2022, 9: 919274.

[51] Linehan E, Fitzgerald D C. Ageing and the immune system: focus on macrophages [J]. Eur J Microbiol Immunol (Bp), 2015, 5 (1): 14 - 24.

[52] Linehan E, Dombrowski Y, Snoddy R, et al. Aging impairs peritoneal but not bone marrow-derived macrophage phagocytosis [J]. Aging Cell, 2014, 13 (4): 699 - 708.

[53] Martinez F O, Helming L, Milde R, et al. Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages: similarities and differences [J]. Blood, 2013, 121 (9): e57 - 69.

[54] Behmoaras J, Gil J. Similarities and interplay between senescent cells and macrophages [J]. J Cell Biol, 2021, 220 (2).

[55] Eggert T, Wolter K, Ji J, et al. Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression [J]. Cancer Cell, 2016, 30 (4): 533 - 47.

[56] Kai K, Komohara Y, Esumi S, et al. Macrophage/microglia-derived IL-1β induces glioblastoma growth via the STAT3/NF-κB pathway [J]. Hum Cell, 2022, 35 (1): 226 - 37.

[57] Gao H, Nepovimova E, Adam V, et al. Age-associated changes in innate and adaptive immunity: role of the gut microbiota [J]. Front Immunol, 2024, 15: 1421062.

[58] Piskor E M, Ross J, Möröy T, et al. Myc-Interacting Zinc Finger Protein 1 (Miz-1) Is Essential to Maintain Homeostasis and Immunocompetence of the B Cell Lineage [J]. Biology (Basel), 2022, 11 (4).

[59] Marin I, Boix O, Garcia-Garijo A, et al. Cellular Senescence Is Immunogenic and Promotes Antitumor Immunity [J]. Cancer Discov, 2023, 1 3 (2): 410 - 31.

[60] Chakraborty M, Chu K, Shrestha A, et al. Mechanical Stiffness Controls Dendritic Cell Metabolism and Function [J]. Cell Rep, 2021, 34 (2): 108609.

[61] Zhang C, Lei L, Yang X, et al. Single-cell sequencing reveals antitumor characteristics of intratumoral immune cells in old mice [J]. J Immunother Cancer, 2021, 9 (10).

[62] Zaretsky J M, Garcia-Diaz A, Shin D S, et al. Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma [J]. N Engl J Med, 2016, 375 (9): 819 - 29.

[63] Maggiorani D, Le O, Lisi V, et al. Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment [J]. Nat Commun, 2024, 15 (1): 2435.

[64] Li Y, Li F, Xu L, et al. Single cell analyses reveal the PD-1 blockade response-related immune features in hepatocellular carcinoma [J]. Theranostics, 2024, 14 (9): 3526 - 47.

[65] Song M, Ping Y, Zhang K, et al. Low-Dose IFNγ Induces Tumor Cell Stemness in Tumor Microenvironment of Non-Small Cell Lung Cancer [J]. Cancer Res, 2019, 79 (14): 3737 - 48.

[66] Ferrara R, Naigeon M, Auclin E, et al. Circulating T-cell Immunosenescence in Patients with Advanced Non-small Cell Lung Cancer Treated with Single-agent PD-1/PD-L1 Inhibitors or Platinum-based Chemotherapy [J]. Clin Cancer Res, 2021, 27 (2): 492 - 503.

[67] Franco F, Jaccard A, Romero P, et al. Metabolic and epigenetic regulation of T-cell exhaustion [J]. Nat Metab, 2020, 2 (10): 1001 - 12.

[68] Matsuda S, Revandkar A, Dubash T D, et al. TGF-β in the microenvironment induces a physiologically occurring immune-suppressive senescent state [J]. Cell Rep, 2023, 42 (3): 112129.

[69] Wu Z, Uhl B, Gires O, et al. A transcriptomic pan-cancer signature for survival prognostication and prediction of immunotherapy response based on endothelial senescence [J]. J Biomed Sci, 2023, 30 (1): 21.

[70] Gao B, Wang Y, Lu S. Cellular senescence affects energy metabolism, immune infiltration and immunotherapeutic response in hepatocellular carcinoma [J]. Sci Rep, 2023, 13 (1): 1137.

[71] Wang Y, Dai L, Huang R, et al. Prognosis signature for predicting the survival and immunotherapy response in esophageal carcinoma based on cellular senescence-related genes [J]. Front Oncol, 2023, 13: 1203351.

[72] Liu X, Si F, Bagley D, et al. Blockades of effector T cell senescence and exhaustion synergistically enhance antitumor immunity and immunotherapy [J]. J Immunotherapy Cancer, 2022, 10 (10).

[73] Zhang F, Guo J, Yu S, et al. Cellular senescence and metabolic reprogramming: Unraveling the intricate crosstalk in the immunosuppressive tumor microenvironment [J]. Cancer Commun (Lond), 2024, 44 (9): 929 - 66.

[74] Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors [J]. Aging Cell, 2016, 15 (3): 428 - 35.

[75] Jiang B, Zhang W, Zhang X, et al. Targeting senescent cells to reshape the tumor microenvironment and improve anticancer efficacy [J]. Semin Cancer Biol, 2024, 101: 58 - 73.

[76] Muñoz-Espín D, Rovira M, Galiana I, et al. A versatile drug delivery system targeting senescent cells [J]. EMBO Mol Med, 2018, 10 (9).

[77] Amor C, Feucht J, Leibold J, et al. Senolytic CAR T cells reverse senescence-associated pathologies [J]. Nature, 2020, 583 (7814): 127 - 32.

[78] Troiani M, Colucci M, D'ambrosio M, et al. Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer [J]. Nat Commun, 2022, 13 (1): 2177.

[79] Ye J, Baer J M, Faget D V, et al. Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression [J]. Cancer Discov, 2024, 14 (7): 1302 - 23.

[80] Laberge R M, Sun Y, Orjalo A V, et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation [J]. Nat Cell Biol, 2015, 17 (8): 1049 - 61.

[81] Moiseeva O, Deschênes-Simard X, St-Germain E, et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation [J]. Aging Cell, 2013, 12 (3): 489 - 98.

[82] Zhao B, Wu B, Feng N, et al. Aging microenvironment and antitumor immunity for geriatric oncology: the landscape and future implications [J]. J Hematol Oncol, 2023, 16 (1): 28.

[83] Wang Z, Chen Y, Fang H, et al. Reprogramming cellular senescence in the tumor microenvironment augments cancer immunotherapy through multifunctional nanocrystals [J]. Sci Adv, 2024, 10 (44): eadp7022.

[84] Ghosh A, Michels J, Mezzadra R, et al. Increased p53 expression induced by APR-246 reprograms tumor-associated macrophages to augment immune checkpoint blockade [J]. J Clin Invest, 2022, 132 (18).

[85] Law A M K, Valdes-Mora F, Gallego-Ortega D. Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer [J]. Cells, 2020, 9 (3).