1125P - Identification of a subset of metastatic melanoma patients demonstrating germline determined insensitivity to immunotherapy

Background

Long-term clinical outcomes post immune checkpoint blockade (ICB) for metastatic melanoma (MM) are highly variable. Whilst this is in part reflects inter-tumour heterogeneity, the degree patient germline genetic variation influences ICB responses is poorly characterised. Previous pan-tumour patient cohort studies suggested that homozygosity at Class I MHC alleles is associated with reduced survival post ICB, although these observations have not been reproduced in meta-analyses. Here we explore the relationship between homozygosity at one, two and three alleles at Class I MHC in a longitudinal follow-up cohort of patients receiving ICB for MM, integrating observations with immunological and transcriptomic data at single-cell resolution.

Methods

232 MM patients receiving standard of care ICB were HLA typed using genome-wide genotyping and followed for up to 9 years. Pre-treatment and on treatment CD8 T cells RNA and T cell receptor (TCR) sequencing of was performed for all samples (n>500), as well as focused single-cell RNA seq. The relationship between homozygosity at HLA-A, HLA-B and HLA-C and survival parameters were explored with results integrated with transcriptomic and immunophenotyping.

Results

50.9% of patients survived for >5 years. Notably, no effect of homozygosity at either one or two Class I HLA alleles on outcomes was noted (60.5% vs. 49.8% - no homozygosity, P=0.17). However, patients homozygous at three alleles (3.0% cohort) have catastrophic outcomes, independent of tumour features, with 1 year survival 17.8% vs. 75.2%, P<0.0001. Pre-treatment these patients have reduced CD8 TCR diversity, and marked immune dysregulation. Single-cell RNA sequencing demonstrates impaired responses to ICB from treatment initiation.

Conclusions

Understanding ICB resistance is of vital importance in stratifying MM treatments. We find homozygosity at one or two Class I MHC alleles does not impact outcomes. Conversely, we demonstrate a subset of MM patients have homozygosity at all three Class I MHC alleles. They show markedly impaired immunological and transcriptomic responses to ICB, with very poor clinical outcomes. This work marks the first description of germline encoded ICB resistance.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

University of Oxford.

Funding

Wellcome Trust, Cancer Research UK.

Disclosure

All authors have declared no conflicts of interest.