Toxicology International (Formerly Indian Journal of Toxicology)

Open Access Open Access  Restricted Access Subscription Access
Open Access Open Access Open Access  Restricted Access Restricted Access Subscription Access

Prospects of Combinatorial Approach Involving ICD Induction and Adenosine A2A Receptor Pathway Inhibition to Improve Cancer Immunotherapy


Affiliations
1 SRM College of Pharmacy, SRM Institute of Science and Technology (SRMIST), Kattankulathur, Chennai – 603203, Tamil Nadu, India
     

   Subscribe/Renew Journal


The purpose of this review is to discuss and summarize the prospects of combinatorial approach involving immunogenic cell death induction and immunosuppressive adenosine A2A receptor pathway inhibition in enhancing anti-tumor immunity. Majority of chemotherapeutic agents can elicit antitumor immunity and modulate the composition, density, function, and distribution of Tumor Infiltrating Lymphocytes (TILs), to influence differential therapeutic responses and prognosis in cancer patients. Accumulating evidence indicates that the clinical success of these agents not only dependents on their cytotoxic activity but also by the enhancement of pre-existing immunity. Over expression of CD39 or CD73 enzymes has been implicated in limiting the ICD caused by chemotherapeutic agents like anthracyclines and oxaliplatin. Conversion of ATP released by chemotherapeutic drugs into adenosine dampens its capacity to attract antigen presenting cells including Dendritic Cells (DC) into the proximity of dying and dead cells. In addition, released adenosine exits potent immunosuppressive activities on different immune cells through A2A receptors in the TME and contributes to the resistance against chemotherapy. Resistance either intrinsic or acquired is the major hurdle for most of the therapeutic interventions. In order to enhance immunogenic cell death by chemotherapeutic agents, it has become clear that blockade of adenosine production or its signaling need to be specifically targeted as they represent highly resistant mechanisms. Given the prominent role of adenosine mediated immune suppression and resistance to ICD induction in TME, combination strategies that involve ICD induction and adenosine signaling blockade are further warranted.

Keywords

A2A Receptor, Adenosine, Anti-Tumor Immune Response, Cancer Immunotherapy, Chemotherapy, Immunogenic Cell Death.
User
Subscription Login to verify subscription
Notifications
Font Size

  • Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin. 2018; 68(6):394-424. https://doi.org/10.3322/caac.21492. PMid:30207593.

  • Kruger S, Ilmer M, Kobold S, et al. Advances in cancer immunotherapy 2019-latest trends. JECCR. 2019; 38(1):1-11. https://doi.org/10.1186/s13046-019-1266-0. PMid:31217020 PMCid:PMC6585101.

  • Chevolet I, Speeckaert R, Schreuer M, et al. Characterization of the in vivo immune net work of IDO, tryptophan metabolism, PD-L1, and CTLA-4 in circulating immune cells in melanoma. Oncoimmunology. 2015; 4(3):e982382. https://doi.org/10.4161/2162402X.2014.982382. PMid:25949897 PMCid:PMC4404886.

  • Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017; 168(4):707-723. https://doi.org/10.1016/j.cell.2017.01.017. PMid:28187290 PMCid:PMC5391692.

  • Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. NEJM. 2017; 377(25):2500. https://doi.org/10.1056/NEJMc1713444. PMid:29262275 PMCid:PMC6549688.

  • Boumber Y. Tumor mutational burden (TMB) as a bio-marker of response to immunotherapy in small cell lung cancer. J. Thorac. Dis.. 2018; 10(8):4689. https://doi.org/10.21037/jtd.2018.07.120. PMid:30233840 PMCid:PMC6129910.

  • Vareki SM. High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors. J. Immunother. Cancer. 2018; 6(1):1-5. https://doi.org/10.1186/s40425-018-0479-7. PMid:30587233 PMCid:PMC6307306.

  • Campoli M, Ferrone S. HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance. Oncogene. 2008; 27(45):5869-5885. https://doi.org/10.1038/onc.2008.273. PMid:18836468 PMCid:PMC2729106.

  • Beatty GL, Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin. Cancer Res. 2015; 21(4):687-692. https://doi.org/10.1158/1078-0432.CCR-14-1860. PMid:25501578 PMCid:PMC4334715.

  • Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol.. 2013; 31:51-72. https://doi.org/10.1146annurev-immunol-032712-100008. PMid:23157435.

  • Kepp O, Senovilla L, Vitale I, et al. Consensus guide-lines for the detection of immunogenic cell death. Oncoimmunology. 2014; 3(9):e955691.

  • Rubartelli A, Lotze MT. Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol. 2007; 28(10):429-436. https://doi.org/10.1016/j.it.2007.08.004. PMid:17845865.

  • Radogna F, Diederich M. Stress-induced cellular responses in immunogenic cell death: Implications for cancer immunotherapy. Biochem. Pharmacol. 2018; 153:12-23. https://doi.org/10.1016/j.bcp.2018.02.006. PMid:29438676.

  • Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P. Immunogenic cell death and DAMPs in cancer therapy. Nat. Rev. Cancer 2012; 12(12):860-875. https://doi.org/10.1038/nrc3380. PMid:23151605.

  • Nelson BH. New insights into tumor immunity revealed by the unique genetic and genomic aspects of ovarian cancer. Curr. Opin. Immunol. 2015; 33:93-100. https://doi.org/10.1016/j.coi.2015.02.004. PMid:25710852.

  • Romero AI, Chaput N, Poirier-Colame V, et al. Regulation of CD4+ NKG2D+ Th1 cells in patients with metastatic melanoma treated with sorafenib: role of IL-15Rα and NKG2D triggering. Cancer Res. 2014; 74(1):68-80. https://doi.org/10.1158/0008-5472.CAN-13-1186.PMid:24197135.

  • Bansal N, Adams MJ, Ganatra S, et al. Strategies to prevent anthracycline-induced cardiotoxicity in cancer survivors. Cardio-oncology. 2019; 5(1):1-22. https://link.springer.com/article/10.1186/s40959-019-0054-5, https://doi.org/10.1186/s40959-019-0054-5. PMid:32154024 PMCid:PMC7048046.

  • Tewey K, Rowe T, Yang L, Halligan B, Liu L-F. Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science. 1984; 226(4673):466-468. https://doi.org/10.1126/science.6093249. PMid:6093249.

  • Guo C, Manjili MH, Subjeck JR, Sarkar D, Fisher PB, Wang X-Y. Therapeutic cancer vaccines: past, present, and future. Adv. Cancer Res. 2013; 119:421-475. https://doi.org/10.1016/B978-0-12-407190-2.00007-1. PMid:23870514 PMCid:PMC3721379.

  • Giglio P, Gagliardi M, Tumino N, et al. PKR and GCN2 stress kinases promote an ER stress-independent eIF2α phosphorylation responsible for calreticulin exposure in melanoma cells. Oncoimmunology. 2018; 7(8):e1466765. https://doi.org/10.1080/2162402X.2018.1466765. PMid:30221067 PMCid:PMC6136861.

  • Sukkurwala A, Martins I, Wang Y, et al. Immunogenic calreticulin exposure occurs through a phylogenetically conserved stress pathway involving the chemo kine CXCL8. Cell Death Differ. 2014; 21(1):59-68. https://doi.org/10.1038/cdd.2013.73. PMid:23787997 PMCid:PMC3857625.

  • Reshetnikov V, Arkhypov A, Julakanti PR, Mokhir A. A cancer specific oxaliplatin-releasing Pt (iv)-prodrug. Dalton Trans. 2018; 47(19):6679-6682. https://doi.org/10.1039/C8DT01458B. PMid:29708261.

  • Tesniere A, Schlemmer F, Boige V, et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene. 2010;29(4):482-491. https://doi.org/10.1038/onc.2009.356. PMid:19881547.

  • Sagwal SK, Pasqual-Melo G, Bodnar Y, Gandhirajan RK, Bekeschus S. Combination of chemotherapy and physi cal plasma elicits melanoma cell death via upregulation of SLC22A16. Cell Death Dis. 2018; 9(12):1-13. https://doi.org/10.1038/s41419-018-1221-6. PMid:30518936 PMCid:PMC6281583.

  • Pfirschke C, Engblom C, Rickelt S, et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity. 2016; 44(2):343-354. https://doi.org/10.1016/j.immuni.2015.11.024. PMid:26872698 PMCid:PMC4758865.

  • Martins I, Kepp O, Schlemmer F, et al. Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress. Oncogene. 2011; 30(10):1147-1158. https://doi.org/10.1038/onc.2010.500. PMid:21151176.

  • Martins I, Wang Y, Michaud M, et al. Molecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ. 2014; 21(1):79-91. https://doi.org/10.1038/cdd.2013.75. PMid:23852373 PMCid:PMC3857631.

  • Demontoux L, Derangere V, Pilot T, et al. Hypotonic stress enhances colon cancer cell death induced by platinum derivatives and immunologically improves antitumor efficacy of intraperitoneal chemotherapy. Int. J. Cancer. 2019; 145(11):3101-3111. https://doi.org/10.1002/ijc.32590. PMid:31344262.

  • Martins I, Tesniere A, Kepp O, et al. Chemotherapy induces ATP release from tumor cells. Cell cycle. 2009; 8(22):3723-3728. https://doi.org/10.4161/cc.8.22.10026. PMid:19855167.

  • Aranda F, Bloy N, Pesquet J, et al. Immune-dependent antineoplastic effects of cisplatin plus pyridoxine in non-small-cell lung cancer. Oncogene. 2015; 34(23):3053-3062. https://doi.org/10.1038/onc.2014.234. PMid:25065595.

  • Di Blasio S, Wortel IM, van Bladel DA, et al. Human CD1c+ DCs are critical cellular mediators of immune responses induced by immunogenic cell death. Oncoimmunology. 2016; 5(8):e1192739. https://doi.org/10.1080/2162402X.2016.1192739. PMid:27622063 PMCid:PMC5007971.

  • Sun F, Cui L, Li T, Chen S, Song J, Li D. Oxaliplatin induces immunogenic cells death and enhances therapeutic efficacy of checkpoint inhibitor in a model of murine lung carcinoma. J. Recept. Signal Transduct. 2019; 39(3):208-214. https://doi.org/10.1080/10799893.2019.1655050. PMid:31441696.

  • Hayashi K, Nikolos F, Lee Y, et al. Tipping the immune-stimulatory and inhibitory DAMP balance to harness immunogenic cell death. Nat. Commun. 2020; 11(1):1-13. https://doi.org/10.1038/s41467-020-19970-9. PMid:33288764 PMCid:PMC7721802

  • Liu W, Fowler D, Smith P, Dalgleish A. Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br. J. Cancer. 2010; 102(1):115-123. https://doi.org/10.1038/sj.bjc.6605465. PMid:19997099 PMCid:PMC2813751.

  • Cottone L, Capobianco A, Gualteroni C, et al. 5‐Fluorouracil causes leukocytes attraction in the peritoneal cavity by activating autophagy and HMGB1.release in colon carcinoma cells. Int. J. Cancer. 2015; 136(6):1381-1389. https://doi.org/10.1002/ijc.29125. PMid:25098891.

  • Yamamura Y, Tsuchikawa T, Miyauchi K, et al. The key role of calreticulin in immunomodulation induced by chemotherapeutic agents. Int. J. Clin. Oncol. 2015; 20(2):386-394. https://doi.org/10.1007/s10147-014-0719-x. PMid:24972573.

  • Geary SM, Lemke CD, Lubaroff DM, Salem AK. The combination of a low-dose chemotherapeutic agent, 5-fluorouracil, and an adenoviral tumor vaccine has a synergistic benefit on survival in a tumor model system. PloS one. 2013; 8(6):e67904. https://doi.org/10.1371/journal.pone.0067904. PMid:23840786 PMCid:PMC3695864.

  • Wang Q, Ju X, Wang J, Fan Y, Ren M, Zhang H. Immunogenic cell death in anticancer chemotherapy and its impact on clinical studies. Cancer Lett. 2018; 438:17-23. https://doi.org/10.1016/j.canlet.2018.08.028. PMid:30217563.

  • Radogna F, Dicato M, Diederich M. Natural modulators of the hallmarks of immunogenic cell death. Biochem. Pharmacol. 2019; 162:55-70. https://doi.org/10.1016/j.bcp.2018.12.016. PMid:30615863.

  • Diederich M, Muller F, Cerella C. Cardiac glycosides: From molecular targets to immunogenic cell death. Biochem. Pharmacol. 2017; 125:1-11. https://doi.org/10.1016/j.bcp.2016.08.017. PMid:27553475.

  • Menger L, Vacchelli E, Adjemian S, et al. Cardiac glycosides exert anticancer effects by inducing immunogenic cell death. Sci. Transl. Med. 2012; 4(143):143ra99-143ra99. https://doi.org/10.1126/scitranslmed.3003807. PMid:22814852.

  • Pol J, Vacchelli E, Aranda F, et al. Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy. Oncoimmunology. 2015; 4(4):e1008866. https://doi.org/10.1080/2162402X.2015.1008866. PMid:26137404 PMCid:PMC4485780.

  • Fanale D, Bronte G, Passiglia F, et al. Stabilizing versus destabilizing the microtubules: a double-edge sword for an effective cancer treatment option? Anal. Cell. Pathol. 2015; 2015. https://doi.org/10.1155/2015/690916. PMid:26484003 PMCid:PMC4592889.

  • Wen C-C, Chen H-M, Chen S-S, et al. Specific micro-tubule-depolymerizing agents augment efficacy of dendritic cell-based cancer vaccines. J. Biomed. Sci. 2011; 18(1):1-15. https://doi.org/10.1186/1423-0127-18-44. PMid:21689407 PMCid:PMC3141632.

  • Cragg GM, Pezzuto JM. Natural products as a vital source for the discovery of cancer chemotherapeutic and chemopreventive agents. Med Princ Pract. 2016; 25(Suppl. 2):41-59. https://doi.org/10.1159/000443404. PMid:26679767 PMCid:PMC5588531.

  • Pellicciotta I, Yang C-PH, Goldberg GL, Shahabi S. Epothilone B enhances Class I HLA and HLA-A2 surface molecule expression in ovarian cancer cells. Gynecol. Oncol. 2011;122(3):625-631. https://doi.org/10.1016/j.ygyno.2011.05.007. PMid:21621254.

  • Senovilla L, Vitale I, Martins I, et al. An immunosurveillance mechanism controls cancer cell ploidy. Science. 2012; 337(6102):1678-1684. https://doi.org/10.1126/science.1224922. PMid:23019653.

  • Davids LM, Kleemann B, Kacerovska D, Pizinger K, Kidson SH. Hypericin phototoxicity induces different modes of cell death in melanoma and human skin cells. J. Photochem. Photobiol. B. 2008; 91(2-3):67-76. https://doi.org/10.1016/j.jphotobiol.2008.01.011. PMid:18342534.

  • Garg AD, Krysko DV, Vandenabeele P, Agostinis P. Hypericin-based photodynamic therapy induces surface exposure of damage-associated molecular patterns like HSP70 and calreticulin. Cancer Immunol. Immunother. 2012; 61(2):215-221. https://doi.org/10.1007/s00262-011-1184-2. PMid:22193987.

  • Chen X, Yang L, Zhang N, et al. Shikonin, a component of Chinese herbal medicine, inhibits chemokine receptor function and suppresses human immunodeficiency virus type 1. Antimicrob Agents Chemothe. 2003; 47(9):2810-2816. https://doi.org/10.1128/AAC.47.9.2810-2816.2003. PMid:12936978 PMCid:PMC182643.

  • Chen H-M, Wang P-H, Chen S-S, et al. Shikonin induces immunogenic cell death in tumor cells and enhances dendritic cell-based cancer vaccine. Cancer Immunol. Immunother. 2012; 61(11):1989-2002. https://doi.org/10.1007/s00262-012-1258-9. PMid:22527248.

  • Lin T-J, Liang W-M, Hsiao P-W, et al. Rapamycin promotes mouse 4T1 tumor metastasis that can be reversed by a dendritic cell-based vaccine. PloS One. 2015; 10(10):e0138335. https://doi.org/10.1371/journal.pone.0138335. PMid:26426423 PMCid:PMC4591294.

  • Tang W, Guo Z, Cao Z, et al. d-Sedoheptulose-7-phosphate is a common precursor for the heptoses of septacidin and hygromycin B. Proc. Natl. Acad. Sci. 2018; 115(11):2818-2823. https://doi.org/10.1073/pnas.1711665115. PMid:29483275 PMCid:PMC5856511.

  • Sukkurwala AQ, Adjemian S, Senovilla L, et al. Screening of novel immunogenic cell death inducers within the NCI Mechanistic Diversity Set. Oncoimmunology. 2014; 3(4):e28473. https://doi.org/10.4161/onci.28473. PMid:25050214 PMCid:PMC4063139.

  • Yang Y, Li X-J, Chen Z, et al. Wogonin induced calreticulin/annexin A1 exposure dictates the immunogenicity of cancer cells in a PERK/AKT dependent manner. PLoS One. 2012; 7(12):e50811. https://doi.org/10.1371/journal.pone.0050811. PMid:23251389 PMCid:PMC3520942.

  • Ramanathapuram LV, Hahn T, Dial SM, Akporiaye ET. Chemo-immunotherapy of breast cancer using vesiculated α-tocopheryl succinate in combination with dendritic cell vaccination. Nutr. Cancer. 2005; 53(2):177-193. https://doi.org/10.1207/s15327914nc5302_7. PMid:16573379.

  • D’Eliseo D, Manzi L, Velotti F. Capsaicin as an inducer of damage-associated molecular patterns (DAMPs) of immunogenic cell death (ICD) in human bladder cancer cells. Cell Stress Chaperones. 2013; 18(6):801-808. https://doi.org/10.1007/s12192-013-0422-2. PMid:23580156 PMCid:PMC3789874.

  • D’Eliseo D, Di Renzo L, Santoni A, Velotti F. Docosahexaenoic acid (DHA) promotes immunogenic apoptosis in human multiple myeloma cells, induces autophagy and inhibits STAT3 in both tumor and dendritic cells. Genes cancer. 2017; 8(1-2):426. https://doi.org/10.18632/genesandcancer.131. PMid:28435516 PMCid:PMC5396621.

  • Obeid M, Panaretakis T, Tesniere A, et al. Leveraging the immune system during chemotherapy: moving calreticulin to the cell surface converts apoptotic death from “silent” to immunogenic. Cancer Res. 2007; 67(17):7941-7944. https://doi.org/10.1158/0008-5472.CAN-07-1622. PMid:17804698.

  • Wolberg G, Zimmerman TP, Hiemstra K, Winston M, Chu L-C. Adenosine inhibition of lymphocyte-mediated cytolysis: possible role of cyclic adenosine monophosphate. Science. 1975; 187(4180):957-959. https://doi.org/10.1126/science.167434. PMid:167434.

  • Di Virgilio F, Adinolfi E. Extracellular purines, purinergic receptors and tumor growth. Oncogene. 2017; 36(3):293-303. https://doi.org/10.1038/onc.2016.206. PMid:27321181 PMCid:PMC5269532.

  • Sitkovsky MV, Lukashev D, Apasov S, et al. Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol. 2004; 22:657-682. https://doi.org/10.1146/annurev.immunol.22.012703.104731. PMid:15032592.

  • Blay J, White TD, Hoskin DW. The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res. 1997; 57(13):2602-2605.

  • Eltzschig HK. Extracellular Adenosine Signaling in Molecular Medicine. Springer; 2013. https://doi.org/10.1007/s00109-013-0999-z. PMid:23338058 PMCid:PMC3563678.

  • Vigano S, Alatzoglou D, Irving M, et al. Targeting adenosine in cancer immunotherapy to enhance T-cell function. Front. Immunol. 2019; 10:925. https://doi.org/10.3389/fimmu.2019.00925. PMid:31244820 PMCid:PMC6562565.

  • Ohta A, Gorelik E, Prasad SJ, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc. Natl. Acad. Sci. 2006; 103(35):13132-13137. https://doi.org/10.1073/pnas.0605251103. PMid:16916931 PMCid:PMC1559765.

  • Hasko G, Pacher P. A2A receptors in inflammation and injury: lessons learned from transgenic animals. J. Leukoc. Biol. 2008; 83(3):447-455. https://doi.org/10.1189/jlb.0607359. PMid:18160539 PMCid:PMC2268631.

  • Rossy J, Williamson DJ, Gaus K. How does the kinase Lck phosphorylate the T cell receptor? Spatial organization as a regulatory mechanism. Front. Immunol. 2012; 3:167.https://doi.org/10.3389/fimmu.2012.00167.

  • Linnemann C, Schildberg FA, Schurich A, et al. Adenosine regulates CD8 T‐cell priming by inhibition of membrane‐proximal T‐cell receptor signalling. Immunology. 2009; 128(1pt2):e728-e737. https://doi.org/10.1111/j.1365-2567.2009.03075.x. PMid:19740334 PMCid:PMC2753927.

  • Leone RD, Emens LA. Targeting adenosine for cancer immunotherapy. J. Immunother. Cancer. 2018; 6(1):1-9. https://doi.org/10.1186/s40425-018-0360-8. PMid:29914571 PMCid:PMC6006764.

  • Jimenez JL, Punzón C, Navarro Jn, Munoz-Fernandez MA, Fresno M. Phosphodiesterase 4 inhibitors prevent cytokine secretion by T lymphocytes by inhibiting nuclear factor-κB and nuclear factor of activated T cells activation. J. Pharmacol. Exp. 2001; 299(2):753-759.

  • Cekic C, Linden J. Purinergic regulation of the immune system. Nat. Rev. Immunol. 2016; 16(3):177. https://doi.org/10.1038/nri.2016.4. PMid:26922909.

  • Butler JJ, Mader JS, Watson CL, Zhang H, Blay J, Hoskin DW. Adenosine inhibits activation‐induced T cell expression of CD2 and CD28 co‐stimulatory molecules: role of interleukin‐2 and cyclic AMP signaling pathways. J. Cell. Biochem. 2003; 89(5):975-991. https://doi.org/10.1002/jcb.10562. PMid:12874832.

  • Tej GNVC, Nayak PK. Mechanistic considerations in chemotherapeutic activity of caffeine. Biomed. Pharmacother. 2018; 105:312-319. https://doi.org/10.1016/j.biopha.2018.05.144. PMid:29864619.

  • Bao R, Hou J, Li Y, et al. Adenosine promotes Foxp3 expression in Treg cells in sepsis model by activating JNK/AP-1 pathway. Am. J. Transl. Res. 2016; 8(5):2284.

  • Allard B, Longhi MS, Robson SC, Stagg J. The ecto-nucleotidases CD 39 and CD 73: Novel checkpoint inhibitor targets. Immunol. Rev. 2017; 276(1):121-144. https://doi.org/10.1111/imr.12528. PMid:28258700 PMCid:PMC5338647.

  • Allard D, Turcotte M, Stagg J. Targeting A2 adenosine receptors in cancer. Immunol. Cell Biol. 2017; 95(4):333-339. https://doi.org/10.1038/icb.2017.8. PMid:28174424.

  • Haschemi A, Wagner O, Marculescu R, et al. Cross-regulation of carbon monoxide and the adenosine A2A receptor in macrophages. J. Immunol. Res. 2007; 178(9):5921-5929. https://doi.org/10.4049/jimmunol.178.9.5921. PMid:17442976.

  • Hasko G, Kuhel DG, Chen J-F, et al. Adenosine inhibits IL‐12 and TNF‐α production via adenosine A2A receptor-dependent and independent mechanisms. FASEB J. 2000; 14(13):2065-2074. https://doi.org/10.1096/fj.99-0508com. PMid:11023991.

  • SzabO C, Scott GS, Virág L, et al. Suppression of macrophage inflammatory protein (MIP)‐1α production and collagen‐induced arthritis by adenosine receptor agonists. Br. J. Pharmacol. 1998; 125(2):379-387. https://doi.org/10.1038/sj.bjp.0702040. PMid:9786512 PMCid:PMC1565610.

  • Si Q-s, Nakamura Y, Kataoka K. Adenosine inhibits superoxide production in rat peritoneal macrophages via elevation of cAMP level. Immunopharmacology. 1997; 36(1):1-7. https://doi.org/10.1016/S0162-3109(96)00158-0.

  • Costales MG, Alam MS, Cavanaugh C, Williams KM. Extracellular adenosine produced by ecto-5′-nucleotidase (CD73) regulates macrophage pro-inflammatory responses, nitric oxide production, and favors Salmonella persistence. Nitric Oxide. 2018; 72:7-15. https://doi.org/10.1016/j.niox.2017.11.001. PMid:29108754.

  • Young A, Ngiow SF, Gao Y, et al. A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment. Cancer Res. 2018; 78(4):1003-1016. https://doi.org/10.1158/0008-5472.CAN-17-2826. PMid:29229601.

  • Lokshin A, Raskovalova T, Huang X, Zacharia LC, Jackson EK, Gorelik E. Adenosine-mediated inhibition of the cytotoxic activity and cytokine production by activated natural killer cells. Cancer Res. 2006; 66(15):7758-7765. https://doi.org/10.1158/0008-5472.CAN-06-0478. PMid:16885379.

  • Hatfield SM, Kjaergaard J, Lukashev D, et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci. Transl. Med. 2015; 7(277):277ra30-277ra30. https://doi.org/10.1126/scitranslmed.aaa1260. PMid:25739764 PMCid:PMC4641038.

  • Allard B, Turcotte M, Stagg J. CD73-generated adenosine: orchestrating the tumor-stroma interplay to promote cancer growth. J Biomed Biotechnol. 2012; 2012. https://doi.org/10.1155/2012/485156. PMid:23125525 PMCid:PMC3482007.

  • Beavis PA, Divisekera U, Paget C, et al. Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc. Natl. Acad. Sci. 2013; 110(36):14711-14716. https://doi.org/10.1073/pnas.1308209110. PMid:23964122 PMCid:PMC3767556.

  • Beavis PA, Milenkovski N, Henderson MA, et al. Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T-cell responses. Cancer Immunol. Res. 2015; 3(5):506-517. https://doi.org/10.1158/2326-6066.CIR-14-0211. PMid:25672397.

  • Iannone R, Miele L, Maiolino P, Pinto A, Morello S. Adenosine limits the therapeutic effectiveness of anti-CTLA4 mAb in a mouse melanoma model. Am. J. Cancer Res. 2014; 4(2):172.

  • Loi S, Pommey S, Haibe-Kains B, et al. CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. Proc. Natl. Acad. Sci. 2013; 110(27):11091-11096. https://doi.org/10.1073/pnas.1222251110. PMid:23776241 PMCid:PMC3704029.

  • Vecchio EA, Tan CY, Gregory KJ, Christopoulos A, White PJ, May LT. Ligand-independent adenosine A2B receptor constitutive activity as a promoter of prostate cancer cell proliferation. J. Pharmacol. Exp. 2016; 357(1):36-44. https://doi.org/10.1124/jpet.115.230003. PMid:26791603.

  • Iannone R, Miele L, Maiolino P, Pinto A, Morello S. Blockade of A2b adenosine receptor reduces tumor growth and immune suppression mediated by myeloid-derived suppressor cells in a mouse model of melanoma. Neoplasia. 2013; 15(12): 1400-1409, IN9-IN10. https://doi.org/10.1593/neo.131748. PMid:24403862 PMCid:PMC3884531.

  • Sorrentino C, Miele L, Porta A, Pinto A, Morello S. Myeloid-derived suppressor cells contribute to A2B adenosine receptor-induced VEGF production and angiogenesis in a mouse melanoma model. Oncotarget. 2015; 6(29):27478. https://doi.org/10.18632/oncotar get.4393. PMid:26317647 PMCid:PMC4695003.

  • Tej GNVC, Neogi K, Verma SS, Gupta SC, Nayak PK. Caffeine-enhanced anti-tumor immune response through decreased expression of PD1 on infil trated cytotoxic T lymphocytes. Eur. J. Pharmacol. 2019; 859:172538. https://doi.org/10.1016/j.ejphar.2019.172538. PMid:31310752.

  • Tej GNVC, Neogi K, Nayak PK. Caffeine-enhanced anti-tumor activity of anti-PD1 monoclonal antibody. Int. Immunopharmacol. 2019; 77:106002. https://doi.org/10.1016/j.intimp.2019.106002. PMid:31711939.

  • Hatfield SM, Sitkovsky M. A2A adenosine receptor antagonists to weaken the hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of cancer. Curr. Opin. Pharmacol. 2016; 29:90-96. https://doi.org/10.1016/j.coph.2016.06.009. PMid:27429212 PMCid:PMC4992656.

  • Mediavilla-Varela M, Castro J, Chiappori A, et al. A novel antagonist of the immune checkpoint protein adenosine A2a receptor restores tumor-infiltrating lymphocyte activity in the context of the tumor micro-environment. Neoplasia. 2017; 19(7):530-536. https://doi.org/10.1016/j.neo.2017.02.004. PMid:28582704 PMCid:PMC5458644.

  • Willingham SB, Ho PY, Hotson A, et al. A2AR antagonism with CPI-444 induces antitumor responses and augments efficacy to anti-PD-(L) 1 and anti-CTLA-4 in preclinical models. Cancer Immunol. Res. 2018; 6(10):1136-1149. https://doi.org/10.1158/2326-6066.CIR-18-0056. PMid:30131376.

  • Zhang J, Yan W, Duan W, Wuthrich K, Cheng J. Tumor immunotherapy using A2A adenosine receptor antagonists. Pharmaceuticals. 2020; 13(9):237. https://doi.org/10.3390/ph13090237. PMid:32911819 PMCid:PMC7558881.

  • Michaud M, Sukkurwala AQ, Martins I, Shen S, Zitvogel L, Kroemer G. Subversion of the chemotherapy-induced anticancer immune response by the ecto-ATPase CD39. Oncoimmunology. 2012; 1(3):393-395. https://doi.org/10.4161/onci.19070. PMid:22737627 PMCid:PMC3382873.

  • Mittal D, Sinha D, Barkauskas D, et al. Adenosine 2B receptor expression on cancer cells promotes metastasis. Cancer Res. 2016; 76(15):4372-4382. https://doi.org/10.1158/0008-5472.CAN-16-0544. PMid:27221704.

  • Schindler U, Seitz L, Ashok D, et al. AB928, a dual antagonist of the A2aR and A2bR adenosine receptors, leads to greater immune activation and reduced tumor growth when combined with chemotherapy. Eur. J. Cancer. 2018; 92:S14-S15. https://doi.org/10.1016/j.ejca.2018.01.037.


Abstract Views: 181

PDF Views: 0




  • Prospects of Combinatorial Approach Involving ICD Induction and Adenosine A2A Receptor Pathway Inhibition to Improve Cancer Immunotherapy

Abstract Views: 181  |  PDF Views: 0

Authors

Y. Anil Kumar
SRM College of Pharmacy, SRM Institute of Science and Technology (SRMIST), Kattankulathur, Chennai – 603203, Tamil Nadu, India
V. Chitra
SRM College of Pharmacy, SRM Institute of Science and Technology (SRMIST), Kattankulathur, Chennai – 603203, Tamil Nadu, India

Abstract


The purpose of this review is to discuss and summarize the prospects of combinatorial approach involving immunogenic cell death induction and immunosuppressive adenosine A2A receptor pathway inhibition in enhancing anti-tumor immunity. Majority of chemotherapeutic agents can elicit antitumor immunity and modulate the composition, density, function, and distribution of Tumor Infiltrating Lymphocytes (TILs), to influence differential therapeutic responses and prognosis in cancer patients. Accumulating evidence indicates that the clinical success of these agents not only dependents on their cytotoxic activity but also by the enhancement of pre-existing immunity. Over expression of CD39 or CD73 enzymes has been implicated in limiting the ICD caused by chemotherapeutic agents like anthracyclines and oxaliplatin. Conversion of ATP released by chemotherapeutic drugs into adenosine dampens its capacity to attract antigen presenting cells including Dendritic Cells (DC) into the proximity of dying and dead cells. In addition, released adenosine exits potent immunosuppressive activities on different immune cells through A2A receptors in the TME and contributes to the resistance against chemotherapy. Resistance either intrinsic or acquired is the major hurdle for most of the therapeutic interventions. In order to enhance immunogenic cell death by chemotherapeutic agents, it has become clear that blockade of adenosine production or its signaling need to be specifically targeted as they represent highly resistant mechanisms. Given the prominent role of adenosine mediated immune suppression and resistance to ICD induction in TME, combination strategies that involve ICD induction and adenosine signaling blockade are further warranted.

Keywords


A2A Receptor, Adenosine, Anti-Tumor Immune Response, Cancer Immunotherapy, Chemotherapy, Immunogenic Cell Death.

References





DOI: https://doi.org/10.18311/ti%2F2022%2Fv29i2%2F28974