Association of HLA class I genotype with outcomes of gastrointestinal cancer patients with immunotherapy.

Abstract

e16551 Background: Chowell et al. showed that HLA (human leukocyte antigen) class I (HLA-I) heterozygosity may avail to survival benefit from immune checkpoint blockade (ICB) in advanced cancer patients. Among their cohorts of melanoma patients, patients with the HLA-B44 supertype had improved survival, while the individuals with HLA-B62 supertype had worse outcome. However, these observations were not supported by another study of NSCLC patients treated with immune checkpoint inhibitors (ICIs). Now whether HLA-I genotype can serve as predictive marker for ICB treatment of other malignancies such as gastrointestinal cancer remains unclear. Methods: Tumor tissue samples before immunotherapy as well as related clinical data were collected from 91 Chinese gastrointestinal cancer patients receiving anti-PD-1/PD-L1 inhibitors and/or anti-CTLA-4 antibodies. Genomic features of tumor specimens were characterized by whole exome sequencing (WES) and HLA-I genotyping of normal DNA from peripheral blood cells were performed using WES data. Tumor immune microenvironment signatures were examined by RNA-sequencing targeting 395 immune related genes. Results: We observed that the individuals with HLA-B62 supertype (n = 15) had a significantly shorter PFS (median PFS, 1.83 months versus 3.53 months; HR, 2.3; 95% CI, 1.03-5.0; p= 0.009) than that of those without HLA-B62 supertype (n = 35) in a subgroup of patients with microsatellite stability (MSS, n = 50) and it was not so in other patients with microsatellite instability-high (MSI-H, n = 17) or unknown MSI status (n = 24). Moreover, the patients with B62 supertype and TP53 mutations (n = 15) exhibited more markedly shortened PFS (mPFS, 1.8 months versus 5.57 months; HR, 3.9; 95% CI, 1.5-9.6; p< 0.0001) and OS (mOS, 4.2 months versus 17.3 months; HR, 4.5; 95% CI, 1.5-13.2; p< 0.0001) compared to those patients with non-B62 supertype and TP53 wildtype (n = 26). Furthermore, gene expression levels of certain immune activation related pathways or markers (IFN-γ signature, cytolytic marker, etc.) in the patients with B62 supertype and without B44 supertype (n = 23) were statistically lower ( p< 0.05) than in those patients without B62 supertype (n = 62). Chi-square test revealed no correlation between HLA-B62 supertype and TP53 mutation, MSI status, tumor mutation burden (TMB) or PD-L1 expression. Conclusions: HLA-B62 supertype in combination with TP53 mutations may define a subset of gastrointestinal cancer patients who probably fail to benefit from ICIs, especially in MSS patients.