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

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.

Loss of Human Leukocyte Antigen and Immune Escape in Head and Neck Cancer

“…This phenomenon of immune escape may potentially allow HLA LOH to abrogate the favorable effects of these features on immunotherapy response. In this study, HLA LOH was associated with a higher likelihood of clinical benefit from anti‐PD‐1 treatment – consistent with findings in urothelial cancer and melanoma, 43 but directionally opposite to findings in non‐small cell lung cancer 12 . Because HLA LOH is both a cause of immune evasion (possibly reducing immunotherapy efficacy), and a consequence of immune surveillance (possibly rendering tumors better poised to respond), the effect on treatment response is likely to be context‐dependent.…”