Insignificant effects of loss of heterozygosity in HLA in the efficacy of immune checkpoint blockade treatment

다국어 초록 (Multilingual Abstract)

Background: It is assumed that loss of heterozygosity and allelic copy loss in HLA gene is associated with poor response rates in immune checkpoint inhibitor treatment. H-owever, the accurate extents or consistency in cancer types have not been explored.
Objective: The goal of this study is to investigate quantitative relationship between HLA allelic copy loss and response rates to immune checkpoint inhibitors. Also, tumor microenvironment was computationally assessed in the tumors with HLA copy loss to provide potential mechanisms for the relationships.
Method: A total of 282 whole exome sequencing data from three cohorts of patients who received immune checkpoint blockade immunotherapy were analyzed, including Anti-PDL1 treated in metastatic urothelial cancer (N = 216), anti-PD1 treated metastatic melanoma (N = 26), and anti-CTLA4 treated metastatic melanoma (N = 39). The LOHHLA algorithm was used to calculate allelic copy number loss at each HLA-A, -B, and -C locus, and further determine HLA allelic copy loss status. The HLA copy status and ICB response rates were analyzed for association using Fisher's exact test. The CIBERSORT-absolute algorithm was then used to analyze the patient's immune environment, which represented loss of heterozygosity, using paired matched RNA sequencing data.
Results: Unlike the general expectation, HLA allelic copy loss was not significantly associated with the ICB responses. Moreover, the relationship showed a reversed relationship in HLA-A in the urothelial cancer (better ICB response in HLA copy loss). Regardless of the HLA copy status, the proportion of cytotoxic immune cells in the immune environment of patients was correlated with ICB response, which was higher in the loss of heterozygosity group in the urothelial cohort.
Conclusion: Although the loss of heterozygosity in HLA was generally expected to be an inhibitory factor in the immune treatment response by causing T cell immune evasion, our analysis demonstrates no explicit relationships.

참고문헌 (Reference)

1 Maeurer MJ, "Tumor escape from immune recognition : lethal recurrent melanoma in a patient associated with downregulation of the peptide transporter protein TAP-1 and loss of expression of the immunodominant MART-1/Melan-A antigen" 98 (98): 1633-1641, 1996

2 Gaffney SG, "The landscape of novel and complementary targets for immunotherapy : an analysis of gene expression in the tumor microenvironment" 10 (10): 4532-4545, 2019

3 Callahan MK, "Targeting T cell coreceptors for cancer therapy" 44 (44): 1069-1078, 2016

4 Mariathasan S, "TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells" 554 (554): 544-548, 2018

5 Dobin A, "STAR : ultrafast universal RNA-seq aligner" 29 (29): 15-21, 2013

6 Pasche B, "Role of transforming growth factor beta in cancer" 186 (186): 153-168, 2001

7 Li B, "RSEM : accurate transcript quantification from RNA-Seq data with or without a reference genome" 12 : 323-, 2011

8 Schwartz LH, "RECIST 11-update and clarification: from the RECIST committee" 62 : 132-137, 2016

9 Lawrence H, "RECIST 1.1—Update and clarification: From the RECIST committee" 62132-62137, 2016

10 Chen B, "Profiling tumor infiltrating immune cells with CIBERSORT" 1711 : 243-259, 2018

11 Chen Q, "Production of IL-10 by melanoma cells : examination of its role in immunosuppression mediated by melanoma" 56 (56): 755-760, 1994

12 Chowell D, "Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy" 359 (359): 582-587, 2018

13 Hoof I, "NetMHCpan, a method for MHC class I binding prediction beyond humans" 61 (61): 1-13, 2009

14 Zaretsky JM, "Mutations associated with acquired resistance to PD-1 blockade in melanoma" 375 (375): 819-829, 2016

15 Berger MF, "Melanoma genome sequencing reveals frequent PREX2 mutations" 485 (485): 502-506, 2012

16 Marty R, "MHC-I genotype restricts the oncogenic mutational landscape" 171 (171): 1272-1283, 2017

17 Gao J, "Loss of IFN-γ Pathway genes in tumor cells as a mechanism of resistance to Anti-CTLA-4 therapy" 167 (167): 397-404, 2016

18 Lynch TJ, "Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer : results from a randomized, double-blind, multicenter phase II study" 30 (30): 2046-2054, 2012

19 Franklin C, "Immunotherapy in melanoma : Recent advances and future directions" 43 (43): 604-611, 2017

20 Dejima H, "Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features" 12 (12): 2722-, 2021

21 Rosenberg SA, "IL-2: the first effective immunotherapy for human cancer" 192 (192): 5451-5458, 2014

22 Hugo W, "Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma" 165 (165): 35-44, 2016

23 Snyder A, "Genetic basis for clinical response to CTLA-4 blockade in melanoma" 371 (371): 2189-2199, 2014

24 Chowell D, "Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy" 25 (25): 1715-1720, 2019

25 Yokokawa J, "Enhanced functionality of CD4+CD25(high)FoxP3+ regulatory T cells in the peripheral blood of patients with prostate cancer" 14 (14): 1032-1040, 2008

26 Shukla SA, "Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes" 33 (33): 1152-1158, 2015

27 McGranahan N, "Allele-specific HLA loss and immune escape in lung cancer evolution" 171 (171): 1259-1271, 2017

28 Rizvi NA, "Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer(CheckMate 063) : a phase 2, singlearm trial" 16 (16): 257-265, 2015