Status of programmed death-1/programmed death-ligand 1 inhibitors in combination with vascular endothelial growth factor/vascular endothelial growth factor receptor inhibitors in advanced refractory colorectal cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIU Xu ,  CHENG Liyang , WANG Zhiwei , DING Hongliang , ZHOU Xiangwu

Department of General Surgery, General Hospital of Southern Theater Command of The People’s Liberation Army of China, Guangzhou 510013, P. R. China;

Corresponding author：

CHENG Liyang, Email: chliyang2008@sina.com

Keywords：

programmed death-1/programmed death-ligand 1; immunotherapy; vascular endothelial growth factor/vascular endothelial growth factor receptor; microsatellite instability; colorectal cancer

DOI：

10.7507/1007-9424.202402003

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To analyze the status of applying programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors combined with vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) inhibitors in advanced refractory colorectal cancer. Method The relevant literature on domestic and foreign research in recent years was summarize. Results The discovery of immune checkpoint PD-1/PD-L1 and the clinical application of related drugs have changed the treatment pattern of advanced solid tumors, but PD-1/PD-L1 inhibitors have poor efficacy in mismatch repair prodicient tumors, and most advanced colorectal cancer belongs to this type. The combination of PD-1/PD-L1 inhibitors and VEGF/VEGFR inhibitors can enhance the therapeutic effect in advanced refractory colorectal cancer, and their interaction mechanisms and clinical efficacy are continuously being proven. Conclusions The combination of PD-1/PD-L1 inhibitors and VEGF/VEGFR inhibitors is a promising treatment strategy for advanced refractory colorectal cancer. More studies are needed to further clarify its efficacy.

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1. Qi J, Li M, Wang L, et al. National and subnational trends in cancer burden in China, 2005-20: an analysis of national mortality surveillance data. Lancet Public Health, 2023, 8(12): e943-e955. doi: 10.1016/S2468-2667(23)00211-6.
2. The National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines). Colon carcinoma. Version 1. 2023.
3. Pauken KE, Torchia JA, Chaudhri A, et al. Emerging concepts in PD-1 checkpoint biology. Semin Immunol, 2021, 52: 101480. doi: 10.1016/j.smim.2021.101480.
4. Zhao Y, Harrison DL, Song Y, et al. Antigen-presenting cell-intrinsic PD-1 neutralizes PD-L1 in cis to attenuate PD-1 signaling in T cells. Cell Rep, 2018, 24(2): 379-390.
5. Cai J, Wang D, Zhang G, et al. The role of PD-1/PD-L1 axis in Treg development and function: Implications for cancer immunotherapy. Onco Targets Ther, 2019, 12: 8437-8445.
6. Darvin P, Toor SM, Sasidharan Nair V, et al. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med, 2018, 50(12): 1-11.
7. Le DT, Kim TW, Van Cutsem E, et al. Phase Ⅱ open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol, 2020, 38(1): 11-19.
8. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol, 2017, 18(9): 1182-1191.
9. FDA grants nivolumab accelerated approval for MSI-H or dMMR colorectal cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-nivolumab-accelerated-approval-msi-h-or-dmmr-colorectal-cancer.
10. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication.
11. Kalyan A, Kircher S, Shah H, et al. Updates on immunotherapy for colorectal cancer. J Gastrointest Oncol, 2018, 9(1): 160-169.
12. Lin KX, Istl AC, Quan D, et al. PD-1 and PD-L1 inhibitors in cold colorectal cancer: challenges and strategies. Cancer Immunol Immunother, 2023, 72(12): 3875-3893.
13. Grady WM. Genomic instability and colon cancer. Cancer Metastasis Rev, 2004, 23(1-2): 11-27.
14. de la Chapelle A, Hampel H. Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol, 2010, 28(20): 3380-3387.
15. Li YC, Korol AB, Fahima T, et al. Microsatellites: genomic distribution, putative functions and mutational mechanisms: a review. Mol Ecol, 2002, 11(12): 2453-2465.
16. Olave MC, Graham RP. Mismatch repair deficiency: The what, how and why it is important. Genes Chromosomes Cancer, 2022, 61(6): 314-321.
17. Losso GM, Moraes Rda S, Gentili AC, et al. Microsatellite instability—MSI markers (BAT26, BAT25, D2S123, D5S346, D17S250) in rectal cancer. Arq Bras Cir Dig, 2012, 25(4): 240-244.
18. Cohen R, Rousseau B, Vidal J, et al. Immune checkpoint inhibition in colorectal cancer: Microsatellite instability and beyond. Target Oncol, 2020, 15(1): 11-24.
19. Llosa NJ, Cruise M, Tam A, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov, 2015, 5(1): 43-51.
20. Giannakis M, Mu XJ, Shukla SA, et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep, 2016, 15(4): 857-865.
21. Wu M, Zheng D, Zhang D, et al. Converting immune cold into hot by biosynthetic functional vesicles to boost systematic antitumor immunity. iScience, 2020, 23(7): 101341. doi: 10.1016/j.isci.2020.101341.
22. Loddenkemper C, Nagorsen D, Zeitz M. Foxp3 and microsatellite stability phenotype in colorectal cancer. Gut, 2008, 57(6): 725-726.
23. Grasso CS, Giannakis M, Wells DK, et al. Genetic mechanisms of immune evasion in colorectal cancer. Cancer Discov, 2018, 8(6): 730-749.
24. Bonaventura P, Shekarian T, Alcazer V, et al. Cold tumors: A therapeutic challenge for immunotherapy. Front Immunol, 2019, 10: 168. doi: 10.3389/fimmu.2019.00168.
25. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity, 2013, 39(1): 1-10.
26. Mellman I, Chen DS, Powles T, et al. The cancer-immunity cycle: Indication, genotype, and immunotype. Immunity, 2023, 56(10): 2188-2205.
27. Syed Khaja AS, Toor SM, El Salhat H, et al. Intratumoral FoxP3⁺helios⁺ regulatory T cells upregulating immunosuppressive molecules are expanded in human colorectal cancer. Front Immunol, 2017, 8: 619. doi: 10.3389/fimmu.2017.00619.
28. Oura K, Morishita A, Tani J, et al. Tumor immune microenvironment and immunosuppressive therapy in hepatocellular carcinoma: a review. Int J Mol Sci, 2021, 22(11): 5801. doi: 10.3390/ijms22115801.
29. Lv B, Wang Y, Ma D, et al. Immunotherapy: Reshape the tumor immune microenvironment. Front Immunol, 2022, 13: 844142. doi: 10.3389/fimmu.2022.844142.
30. Voron T, Colussi O, Marcheteau E, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8⁺ T cells in tumors. J Exp Med, 2015, 212(2): 139-148.
31. Mempel TR, Lill JK, Altenburger LM. How chemokines organize the tumour microenvironment. Nat Rev Cancer, 2024, 24(1): 28-50.
32. Ebert PJR, Cheung J, Yang Y, et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity, 2016, 44(3): 609-621.
33. Ferguson SD, Srinivasan VM, Heimberger AB. The role of STAT3 in tumor-mediated immune suppression. J Neurooncol, 2015, 123(3): 385-394.
34. Chow A, Perica K, Klebanoff CA, et al. Clinical implications of T cell exhaustion for cancer immunotherapy. Nat Rev Clin Oncol, 2022, 19(12): 775-790.
35. Opzoomer JW, Sosnowska D, Anstee JE, et al. Cytotoxic chemotherapy as an immune stimulus: a molecular perspective on turning up the immunological heat on cancer. Front Immunol, 2019, 10: 1654. doi: 10.3389/fimmu.2019.01654.
36. Krombach J, Hennel R, Brix N, et al. Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells. Oncoimmunology, 2018, 8(1): e1523097. doi: 10.1080/2162402X.2018.1523097.
37. McLaughlin M, Patin EC, Pedersen M, et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat Rev Cancer, 2020, 20(4): 203-217.
38. Schmidt EV, Chisamore MJ, Chaney MF, et al. Assessment of clinical activity of PD-1 checkpoint inhibitor combination therapies reported in clinical trials. JAMA Netw Open, 2020, 3(2): e1920833. doi: 10.1001/jamanetworkopen.2019.20833.
39. Lee WS, Yang H, Chon HJ, et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med, 2020, 52(9): 1475-1485.
40. Lanitis E, Irving M, Coukos G. Targeting the tumor vasculature to enhance T cell activity. Curr Opin Immunol, 2015, 33: 55-63.
41. Fisher DT, Chen Q, Skitzki JJ, et al. IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells. J Clin Invest, 2011, 121(10): 3846-3859.
42. Barsoum IB, Smallwood CA, Siemens DR, et al. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res, 2014, 74(3): 665-674.
43. Chen J, Jiang CC, Jin L, et al. Regulation of PD-L1: a novel role of pro-survival signalling in cancer. Ann Oncol, 2016, 27(3): 409-416.
44. Facciabene A, Peng X, Hagemann IS, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature, 2011, 475(7355): 226-230.
45. Movahedi K, Laoui D, Gysemans C, et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C^high monocytes. Cancer Res, 2010, 70(14): 5728-5739.
46. Fu C, Jiang A. Dendritic cells and CD8 T cell immunity in tumor microenvironment. Front Immunol, 2018 Dec 20: 9: 3059. doi: 10.3389/fimmu.2018.03059.
47. Terme M, Pernot S, Marcheteau E, et al. VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res, 2013, 73(2): 539-549.
48. Yang J, Yan J, Liu B. Targeting VEGF/VEGFR to modulate antitumor immunity. Front Immunol, 2018, 9: 978. doi: 10.3389/fimmu.2018.00978.
49. Kim CG, Jang M, Kim Y, et al. VEGF-A drives TOX-dependent T cell exhaustion in anti-PD-1-resistant microsatellite stable colorectal cancers. Sci Immunol, 2019, 4(41): eaay0555. doi: 10.1126/sciimmunol.aay0555.
50. Doleschel D, Hoff S, Koletnik S, et al. Regorafenib enhances anti-PD1 immunotherapy efficacy in murine colorectal cancers and their combination prevents tumor regrowth. J Exp Clin Cancer Res, 2021, 40(1): 288. doi: 10.1186/s13046-021-02043-0.
51. Fiegle E, Doleschel D, Koletnik S, et al. Dual CTLA-4 and PD-L1 blockade inhibits tumor growth and liver metastasis in a highly aggressive orthotopic mouse model of colon cancer. Neoplasia, 2019, 21(9): 932-944.
52. Zhou K, Zhang JW, Wang QZ, et al. Apatinib, a selective VEGFR2 inhibitor, improves the delivery of chemotherapeutic agents to tumors by normalizing tumor vessels in LoVo colon cancer xenograft mice. Acta Pharmacol Sin, 2019, 40(4): 556-562.
53. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med, 2020, 382(20): 1894-1905.
54. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med, 2018, 378(24): 2288-2301.
55. Rini BI, Powles T, Atkins MB, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet, 2019, 393(10189): 2404-2415.
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