Abstract
Neopeptide presentation to T cells by both HLA class I and II molecules is necessary for antitumor immune response. Both classes are extremely diverse and different variants have distinct peptide-binding specificities. HLA diversity and certain HLA variants have been suggested to influence antitumor immunity, however, the findings are controversial. As both HLA class I and II molecules have an essential role in the recognition of tumor cells, we examined their joint effect in melanoma patients. We found numerous HLA class I and II allele combinations associated with better or worse survival in metastatic melanoma patients receiving immune checkpoint blockade (ICB) immunotherapy. Moreover, these combinations predicted the survival of ICB-naive patients, too. Importantly, allele combinations had a much stronger and more robust effect than any HLA class I or II variants alone. In the case of beneficial combinations, both HLA class I and II alleles were likely to bind melanoma-associated mutations. Paradoxically, they bound these mutations even stronger in detrimental combinations. Beneficial and detrimental combinations had a diametrical effect on antitumor immune response in primary and metastatic samples. The former was associated with dendritic cell infiltrate in the microenvironment of primary tumors and an active cytotoxic immune response in metastatic samples. On the contrary, detrimental combinations were associated with cytotoxic immune response in primary tumors, while metastases showed signs of immune evasion and ineffective antitumor immunity. Our results provide evidence of the joint effect of HLA class I and II variants on antitumor immunity. The findings also highlight the importance of the timing of immune response during tumor evolution. While beneficial combinations resulted in an effective immune response in metastases only, detrimental ones caused excessive inflammation already in primary tumors leading to immune evasion in metastatic samples.
Citation Format: Benjamin Tamás Papp, Anna Tácia Fülöp, Balázs Koncz, Gergő Mihály Balogh, Dóra Spekhardt, Máté Manczinger. The joint effect of HLA class I and II alleles shapes antitumor immunity in melanoma patients [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A19.
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