16P - Immune checkpoint blockade and HLA-related epistasis in melanoma: Genetic determinants of response and toxicity

Background

Accurate prediction of response and toxicity to immune checkpoint blockade (ICB) remains elusive. Whilst loss of heterozygosity of HLA molecules is an established mechanism of tumour immune-escape, the impact of germline HLA homozygosity is contentious. Autoimmune risk alleles present attractive targets for toxicity-response prediction but interactions with HLA homozygosity are unexplored. Here we examine the effect of germline HLA homozygosity, plus its interaction with autoimmune risk alleles PTPN22 (rs2476601) and IL7 (rs16906115) on overall survival (OS) and toxicity.

Methods

345 patients with melanoma were prospectively recruited for ICB response and toxicity assessment. Clinical, radiological and haematological parameters were recorded. Blood samples were assayed pre-treatment and at multiple timepoints on treatment with flow cytometry, RNA sequencing, TCR/BCR mapping and Olink cytokine assays.

Results

Homozygosity at any of 6 major HLA loci associated with earlier treatment age, particularly in females, whilst class I HLA homozygosity was associated with multiple primary malignancies. IL7 risk allele carriage was more common in males with HLA homozygosity and both PTPN22 and IL7 risk alleles were associated with prognosis-associated monocyte and neutrophil counts. PTPN22 allele status was associated with on treatment naïve T-cell CD4:CD8 ratios, CD8 central and effector memory:naïve ratios and regulatory T cell numbers. Within HLA alleles, HLA-C homozygosity was associated with improved OS, whilst homozygosity at all class I HLA alleles was associated with very poor OS. Strikingly, we detect epistatic effects between HLA homozygosity and PTPN22 and IL7 risk allele carriage, with a weak OS benefit of PTPN22 seen across all patients found to be restricted to those with HLA homozygosity. Similarly, IL7 status demonstrated epistasis with HLA status resulting in significant OS improvement in homozygous patients.

Conclusions

HLA homozygosity across three HLA alleles has profoundly deleterious impact on OS whilst autoimmune risk allele carriage interacts with HLA to impact OS and toxicity. These factors are of relevance to ICB treatment stratification and trial design.

Legal entity responsible for the study

The Fairfax Group, Department of Oncology, University of Oxford.

Funding

Wellcome Trust.

Disclosure

B.P. Fairfax: Financial Interests, Institutional, Advisory Board, I sit on a scientific advisory board for Roche regarding immunotherapy toxicity: Roche; Financial Interests, Institutional, Advisory Board, I have sat on a scientific advisory board for Pathios Therapeutics: Pathios Therapeutics; Financial Interests, Institutional, Invited Speaker, I have given a talk and provided consultancy for Immunocore and may provide further input for their work as a scientific advisor: Immunocore; Financial Interests, Personal, Advisory Board, I have given a talk and provided consultancy for UCB, last in 2022; UCB; Financial Interests, Personal, Invited Speaker, I have provided an educational talk for Bristol Myers Squibb for local Oncology meeting in Birmingham UK and may provide further such talks; BMS; Financial Interests, Personal, Invited Speaker, I have been asked to present my group's work at GSK in 2024: GSK; Financial Interests, Personal, Advisory Board, I have been asked to sit on a scientific advisory board for TCypher BIO: TCypher BIO. All other authors have declared no conflicts of interest.