The interplay of HLA diversity and copy loss, T-cell profiles, and immunotherapy efficacy in colorectal adenocarcinoma.

Abstract

196 Background: HLA Class I (HLA-I) proteins present antigens to CD8+ T-cells to facilitate antitumor responses. The impact of HLA-I diversity on immune checkpoint inhibition (ICI) efficacy is unclear in colorectal cancer (CRC). We explored HLA-I genotypes and loss of heterozygosity (LoH) in relation to T-cell dynamics and ICI efficacy in CRC. Methods: Tumor whole-exome sequencing datasets were from 3 CRC datasets: 580 TCGA patients (pts), 82 pts from a BC Cancer resectable CRC study (VICTORI) and 109 pts from the Canadian Cancer Trials Group CO.26 trial (NCT02870920) comparing durvalumab and tremelimumab (D+T) to supportive care in refractory CRC. POLYSOLVER and LOHHLA were used to determine HLA-I genotypes and LoH status. Samples were labeled somatic LoH or germline homozygosity (Hom) if ≥1 HLA-I gene (HLA-A, B, or C) showed LoH or homozygosity. T-cell populations were inferred using CIBERSORT in TCGA and VICTORI RNA-seq data. In CO.26, T-cell receptor (TCR) Shannon diversity was determined using MiXCR on TCR-seq data. Results: The average rate of LoH and Hom was 24.7% and 25.0%, respectively (dataset and HLA-I-gene rates in table). Rates did not differ by age or sex; however, LoH was more common in white and Asian pts (OR=3.1, 95% CI 1.2-10.6, p=0.015) whereas Hom had no race association. HLA-I supertypes had varied loss prevalence compared to germline: B62 had the highest at 12.5% (95% CI 7.6-19.9) while B08 was lowest at 4.1% (95% CI 1.8-9.2). We next assessed common (>5%) HLA alleles and ICI efficacy. B44:02 and C05:01 were in 13% of pts and associated with reduced overall survival (OS) in pts receiving D+T after correcting for plasma TMB and liver metastases (adjusted hazard ratio (aHR)=3.5, p=0.001, p-interaction=0.005; aHR=3.5, p=0.004, p-int=0.004). These alleles often co-occurred (p<0.001) and B44 was most frequent in white pts (OR=10.7, 95% CI 1.7-440.3, p=0.002). We then examined the role of LoH on immune microenvironment and patient outcomes. LoH in HLA-B and HLA-C correlated with higher expression of each gene (p=0.004; p=0.009). Further, LoH CRCs had higher CD8+ T-cell and active/resting memory CD4+ T-cell scores in VICTORI (p=0.024, p=0.013 respectively) and TCGA (p=0.046, p=0.029). Neither LoH (p=0.13) nor Hom (p=0.86) affected OS in ICI treated CRCs. However, the combo of LoH and low TCR diversity reduced ICI efficacy (HR-int=7.1, p-int=0.01). Conclusions: HLA alleles B44:02 and C05:01 reduced ICI efficacy. HLA-I LoH correlated with higher HLA-I gene expression and active T-cell levels, indicating its selection in T-cell infiltrated tumors. In these tumors, the combo of low TCR diversity and LoH may cause immune evasion and reduced ICI efficacy. CO.26 VICTORI TCGA HLA-I LoH (%) 21.2 28.8 24.9 HLA-I Hom (&) 22.3 25.3 25.5 HLA-A,B,C LoH (%) 16.9, 11,8, 13.1 15.7, 15,8, 22.1 19.1, 17.6, 17.2 HLA-A,B,C Hom (%) 16.8, 4.7, 7.5 14.6, 7.3, 13.9 14.1, 9.1, 12.4