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Current Molecular Medicine

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ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

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Mini-Review Article

Tumor Mutational Burden as a Biomarker of Immunotherapy Response: An Immunogram Approach in Onco-immunology

In Press, (this is not the final "Version of Record"). Available online 01 November, 2023
Author(s): Afzal Ansari, Suman Kumar Ray, Mukul Sharma, Rakesh Rawal* and Pushpendra Singh*
Published on: 01 November, 2023

DOI: 10.2174/0115665240266906231024111920

Price: $95

Abstract

Immune checkpoint inhibitors have revolutionized cancer treatment by allowing T cells to reactivate. Tumor mutational burden (TMB) is a biomarker that has emerged as a viable diagnostic for locating patients who would benefit from immunotherapy in particular cancer types. Greater neo-antigens mean more opportunities for T cell identification, and TMB is clinically linked to better immune checkpoint inhibitors. Tumor foreignness is a cancer immunogram, and TMB can be used as a substitute for foreignness. The role of TMB analysis as an independent predictor of immunotherapy response in the context of immune checkpoint inhibitor medications is the subject of this mini-review.

[1]
Gonzalez H, Hagerling C, Werb Z. Roles of the immune system in cancer: From tumor initiation to metastatic progression. Genes Dev 2018; 32(19-20): 1267-84.
[http://dx.doi.org/10.1101/gad.314617.118] [PMID: 30275043]
[2]
Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer 2019; 19(3): 133-50.
[http://dx.doi.org/10.1038/s41568-019-0116-x] [PMID: 30755690]
[3]
Ray SK, Mukherjee S. Current headway in cancer immunotherapy emphasizing the practice of genetically engineered T cells to target selected tumor antigens. Crit Rev Immunol 2021; 41(1): 23-40.
[http://dx.doi.org/10.1615/CritRevImmunol.2020037044] [PMID: 33822523]
[4]
Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: The beginning of the end of cancer? BMC Med 2016; 14(1): 73.
[http://dx.doi.org/10.1186/s12916-016-0623-5] [PMID: 27151159]
[5]
Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol 2020; 20(11): 651-68.
[http://dx.doi.org/10.1038/s41577-020-0306-5] [PMID: 32433532]
[6]
Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol 2008; 8(1): 59-73.
[http://dx.doi.org/10.1038/nri2216] [PMID: 18097448]
[7]
Fusco MJ, West HJ, Walko CM. Tumor mutation burden and cancer treatment. JAMA Oncol 2021; 7(2): 316.
[http://dx.doi.org/10.1001/jamaoncol.2020.6371] [PMID: 33331847]
[8]
Galuppini F, Dal Pozzo CA, Deckert J, Loupakis F, Fassan M, Baffa R. Tumor mutation burden: From comprehensive mutational screening to the clinic. Cancer Cell Int 2019; 19(1): 209.
[http://dx.doi.org/10.1186/s12935-019-0929-4] [PMID: 31406485]
[9]
Alsaab HO, Sau S, Alzhrani R, et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol 2017; 8: 561.
[http://dx.doi.org/10.3389/fphar.2017.00561] [PMID: 28878676]
[10]
Jiang Y, Chen M, Nie H, Yuan Y. PD-1 and PD-L1 in cancer immunotherapy: Clinical implications and future considerations. Hum Vaccin Immunother 2019; 15(5): 1111-22.
[http://dx.doi.org/10.1080/21645515.2019.1571892] [PMID: 30888929]
[11]
Suspitsyn EN, Sokolenko AP, Imyanitov EN. [Whole exome sequencing in oncology]. Vopr Onkol 2016; 62(6): 713-8.
[PMID: 30695557]
[12]
Kim JY, Kronbichler A, Eisenhut M, et al. Tumor mutational burden and efficacy of immune checkpoint inhibitors: A systematic review and meta-analysis. Cancers 2019; 11(11): 1798.
[http://dx.doi.org/10.3390/cancers11111798] [PMID: 31731749]
[13]
Jardim DL, Goodman A, de Melo Gagliato D, Kurzrock R. The challenges of tumor mutational burden as an immunotherapy biomarker. Cancer Cell 2021; 39(2): 154-73.
[http://dx.doi.org/10.1016/j.ccell.2020.10.001] [PMID: 33125859]
[14]
Klempner SJ, Fabrizio D, Bane S, et al. Tumor mutational burden as a predictive biomarker for response to immune checkpoint inhibitors: A review of current evidence. Oncologist 2020; 25(1): e147-59.
[http://dx.doi.org/10.1634/theoncologist.2019-0244] [PMID: 31578273]
[15]
Fumet JD, Truntzer C, Yarchoan M, Ghiringhelli F. Tumour mutational burden as a biomarker for immunotherapy: Current data and emerging concepts. Eur J Cancer 2020; 131: 40-50.
[http://dx.doi.org/10.1016/j.ejca.2020.02.038] [PMID: 32278982]
[16]
Kage H, Kohsaka S, Tatsuno K, et al. Tumor mutational burden measurement using comprehensive genomic profiling assay. Jpn J Clin Oncol 2022; 52(8): 925-9.
[http://dx.doi.org/10.1093/jjco/hyac063] [PMID: 35482395]
[17]
Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: Results from the phase II KEYNOTE-158 study. J Clin Oncol 2020; 38(1): 1-10.
[http://dx.doi.org/10.1200/JCO.19.02105] [PMID: 31682550]
[18]
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): 11-9.
[http://dx.doi.org/10.1200/JCO.19.02107] [PMID: 31725351]
[19]
Labriola MK, Zhu J, Gupta R, et al. Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma. J Immunother Cancer 2020; 8(1): e000319.
[http://dx.doi.org/10.1136/jitc-2019-000319] [PMID: 32221016]
[20]
Sundar R, Smyth EC, Peng S, Yeong JPS, Tan P. Predictive biomarkers of immune checkpoint inhibition in gastroesophageal cancers. Front Oncol 2020; 10: 763.
[http://dx.doi.org/10.3389/fonc.2020.00763] [PMID: 32500029]
[21]
Heydt C, Rehker J, Pappesch R, et al. Analysis of tumor mutational burden: Correlation of five large gene panels with whole exome sequencing. Sci Rep 2020; 10(1): 11387.
[http://dx.doi.org/10.1038/s41598-020-68394-4] [PMID: 32647293]
[22]
Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 2017; 9(1): 34.
[http://dx.doi.org/10.1186/s13073-017-0424-2] [PMID: 28420421]
[23]
Forschner A, Battke F, Hadaschik D, et al. Tumor mutation burden and circulating tumor DNA in combined CTLA-4 and PD-1 antibody therapy in metastatic melanoma – results of a prospective biomarker study. J Immunother Cancer 2019; 7(1): 180.
[http://dx.doi.org/10.1186/s40425-019-0659-0] [PMID: 31300034]
[24]
Meléndez B, Van Campenhout C, Rorive S, Remmelink M, Salmon I, D’Haene N. Methods of measurement for tumor mutational burden in tumor tissue. Transl Lung Cancer Res 2018; 7(5): 661-7.
[http://dx.doi.org/10.21037/tlcr.2018.08.02] [PMID: 30505710]
[25]
Fancello L, Gandini S, Pelicci PG, Mazzarella L. Tumor mutational burden quantification from targeted gene panels: Major advancements and challenges. J Immunother Cancer 2019; 7(1): 183.
[http://dx.doi.org/10.1186/s40425-019-0647-4] [PMID: 31307554]
[26]
Li Y, Luo Y. Optimizing the evaluation of gene-targeted panels for tumor mutational burden estimation. Sci Rep 2021; 11(1): 21072.
[http://dx.doi.org/10.1038/s41598-021-00626-7] [PMID: 34702927]
[27]
Li JX, Li RZ, Ma LR, et al. Targeting mutant Kirsten rat sarcoma viral oncogene homolog in non-small cell lung cancer: current difficulties, integrative treatments and future perspectives. Front Pharmacol 2022; 13: 875330.
[http://dx.doi.org/10.3389/fphar.2022.875330] [PMID: 35517800]
[28]
Ray SK, Meshram Y, Mukherjee S. Cancer immunology and CAR-T cells: A turning point therapeutic approach in colorectal carcinoma with clinical insight. Curr Mol Med 2021; 21(3): 221-36.
[http://dx.doi.org/10.2174/1566524020666200824103749] [PMID: 32838717]
[29]
Riaz N, Havel JJ, Makarov V, et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 2017; 171(4): 934-949.e16.
[http://dx.doi.org/10.1016/j.cell.2017.09.028] [PMID: 29033130]
[30]
Rizvi NA, Hellmann MD, Snyder A, et al. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science 2015; 348(6230): 124-8.
[http://dx.doi.org/10.1126/science.aaa1348] [PMID: 25765070]
[31]
Niknafs N, Balan A, Cherry C, et al. Persistent mutation burden drives sustained anti-tumor immune responses. Nat Med 2023; 29(2): 440-9.
[http://dx.doi.org/10.1038/s41591-022-02163-w] [PMID: 36702947]
[32]
Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet 2019; 51(2): 202-6.
[http://dx.doi.org/10.1038/s41588-018-0312-8] [PMID: 30643254]
[33]
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science 2013; 339(6127): 1546-58.
[34]
Goodman AM, Kato S, Bazhenova L, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancerstmb predicts response to immunotherapy in diverse cancers. Mol Cancer Ther 2017; 16(11): 2598-608.
[http://dx.doi.org/10.1158/1535-7163.MCT-17-0386] [PMID: 28835386]
[35]
Galanina N, Bejar R, Choi M, et al. Comprehensive genomic profiling reveals diverse but actionable molecular portfolios across hematologic malignancies: Implications for next generation clinical trials. Cancers 2018; 11(1): 11.
[http://dx.doi.org/10.3390/cancers11010011] [PMID: 30583461]
[36]
Bai R, Lv Z, Xu D, Cui J. Predictive biomarkers for cancer immunotherapy with immune checkpoint inhibitors. Biomark Res 2020; 8(1): 34.
[http://dx.doi.org/10.1186/s40364-020-00209-0] [PMID: 32864131]
[37]
Marty R, Kaabinejadian S, Rossell D, et al. MHC-I genotype restricts the oncogenic mutational landscape. Cell 2017; 171(6): 1272-1283.e15.
[http://dx.doi.org/10.1016/j.cell.2017.09.050] [PMID: 29107334]
[38]
Cai Z, Chen J, Yu Z, et al. BCAT2 shapes a noninflamed tumor microenvironment and induces resistance to Anti-PD-1/PD-L1 immunotherapy by negatively regulating proinflammatory chemokines and anticancer immunity. Adv Sci 2023; 10(8): e2207155.
[39]
Li H, Chen J, Li Z, et al. S100A5 attenuates efficiency of anti-PD-L1/PD-1 immunotherapy by inhibiting CD8+ T cell-mediated anti-cancer immunity in bladder carcinoma. Adv Sci 2023; 10(25): e2300110.
[40]
van Dijk N, Funt SA, Blank CU, Powles T, Rosenberg JE, van der Heijden MS. The cancer immunogram as a framework for personalized immunotherapy in urothelial cancer. Eur Urol 2019; 75(3): 435-44.
[http://dx.doi.org/10.1016/j.eururo.2018.09.022] [PMID: 30274701]
[41]
Hendriks LE, Rouleau E, Besse B. Clinical utility of tumor mutational burden in patients with non-small cell lung cancer treated with immunotherapy. Transl Lung Cancer Res 2018; 7(5): 647-60.
[http://dx.doi.org/10.21037/tlcr.2018.09.22] [PMID: 30505709]
[42]
Gabbia D, De Martin S. Tumor mutational burden for predicting prognosis and therapy outcome of hepatocellular carcinoma. Int J Mol Sci 2023; 24(4): 3441.
[http://dx.doi.org/10.3390/ijms24043441] [PMID: 36834851]
[43]
Parra NS, Ross HM, Khan A, et al. Advancements in the diagnosis of hepatocellular carcinoma. J Transl Med 2023; 3(1): 51-65.
[http://dx.doi.org/10.3390/ijtm3010005]
[44]
McGrail DJ, Pilié PG, Rashid NU, et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann Oncol 2021; 32(5): 661-72.
[http://dx.doi.org/10.1016/j.annonc.2021.02.006] [PMID: 33736924]
[45]
Bronte F, Bronte G, Cusenza S, et al. Targeted therapies in hepatocellular carcinoma. Curr Med Chem 2014; 21(8): 966-74.
[http://dx.doi.org/10.2174/09298673113209990234] [PMID: 23992323]
[46]
Campani C, Zucman-Rossi J, Nault JC. Genetics of hepatocellular carcinoma: From tumor to circulating DNA. Cancers 2023; 15(3): 817.
[http://dx.doi.org/10.3390/cancers15030817] [PMID: 36765775]
[47]
Hu J, Chen J, Ou Z, et al. Neoadjuvant immunotherapy, chemotherapy, and combination therapy in muscle-invasive bladder cancer: A multi-center real-world retrospective study. Cell Rep Med 2022; 3(11): 100785.
[http://dx.doi.org/10.1016/j.xcrm.2022.100785] [PMID: 36265483]
[48]
Wan L, Wang Z, Xue J, Yang H, Zhu Y. Tumor mutation burden predicts response and survival to immune checkpoint inhibitors: A meta-analysis. Transl Cancer Res 2020; 9(9): 5437-49.
[http://dx.doi.org/10.21037/tcr-20-1131] [PMID: 35117909]
[49]
Chan TA, Yarchoan M, Jaffee E, et al. Development of tumor mutation burden as an immunotherapy biomarker: Utility for the oncology clinic. Ann Oncol 2019; 30(1): 44-56.
[http://dx.doi.org/10.1093/annonc/mdy495] [PMID: 30395155]
[50]
Mukai S, Kanzaki H, Ogasawara S, et al. Exploring microsatellite instability in patients with advanced hepatocellular carcinoma and its tumor microenvironment. JGH Open 2021; 5(11): 1266-74.
[http://dx.doi.org/10.1002/jgh3.12660] [PMID: 34816012]
[51]
Ray SK, Mukherjee S. Cell free DNA as an evolving liquid biopsy biomarker for initial diagnosis and therapeutic nursing in cancer- an evolving aspect in medical biotechnology. Curr Pharm Biotechnol 2022; 23(1): 112-22.
[http://dx.doi.org/10.2174/1389201021666201211102710] [PMID: 33308128]
[52]
Wu X, Li J, Gassa A, et al. Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma. Int J Biol Sci 2020; 16(9): 1551-62.
[http://dx.doi.org/10.7150/ijbs.44024] [PMID: 32226301]
[53]
Makrooni MA, O’Sullivan B, Seoighe C. Bias and inconsistency in the estimation of tumour mutation burden. BMC Cancer 2022; 22(1): 840.
[http://dx.doi.org/10.1186/s12885-022-09897-3] [PMID: 35918650]
[54]
Sun D, Xu M, Pan C, et al. Systematic assessment and optimizing algorithm of tumor mutational burden calculation and their implications in clinical decision-making. Front Oncol 2022; 12: 972972.
[http://dx.doi.org/10.3389/fonc.2022.972972] [PMID: 36425562]
[55]
Dougherty BA, Lai Z, Hodgson DR, et al. Biological and clinical evidence for somatic mutations in BRCA1 and BRCA2 as predictive markers for olaparib response in high-grade serous ovarian cancers in the maintenance setting. Oncotarget 2017; 8(27): 43653-61.
[http://dx.doi.org/10.18632/oncotarget.17613] [PMID: 28525389]
[56]
Ptashkin RN, Ewalt MD, Jayakumaran G, et al. Enhanced clinical assessment of hematologic malignancies through routine paired tumor:normal sequencing. medRxiv 2022.
[http://dx.doi.org/10.1101/2022.10.03.22280675]
[57]
Sha D, Jin Z, Budczies J, Kluck K, Stenzinger A, Sinicrope FA. Tumor mutational burden as a predictive biomarker in solid tumors. Cancer Discov 2020; 10(12): 1808-25.
[http://dx.doi.org/10.1158/2159-8290.CD-20-0522] [PMID: 33139244]

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