Oliveira et al. used scRNAseq and CITEseq to characterize CD4+ TILs from human melanomas, and showed that HLA class IIpos melanomas could directly engage and stimulate CD4+ TILs, conferring tumor cells with the ability to directly control immune suppression. HLA class IIneg melanomas indirectly stimulated CD4+ TILs via APCs, leading to either productive or detrimental antitumor responses. Tumors with HLA class Il upregulation were enriched for high TMB, TCRs with direct tumor recognition, clonal expansion of Tregs, and high numbers of CD8+ TILs, whereas HLA class I was frequently downregulated in melanoma.
Contributed by Shishir Pant
ABSTRACT: Within the tumour microenvironment, CD4(+) T cells can promote or suppress antitumour responses through the recognition of antigens presented by human leukocyte antigen (HLA) class II molecules(1,2), but how cancers co-opt these physiologic processes to achieve immune evasion remains incompletely understood. Here we performed in-depth analysis of the phenotype and tumour specificity of CD4(+) T cells infiltrating human melanoma specimens, finding that exhausted cytotoxic CD4(+) T cells could be directly induced by melanoma cells through recognition of HLA class II-restricted neoantigens, and also HLA class I-restricted tumour-associated antigens. CD4(+) T regulatory (T(Reg)) cells could be indirectly elicited through presentation of tumour antigens via antigen-presenting cells. Notably, numerous tumour-reactive CD4(+) T(Reg) clones were stimulated directly by HLA class II-positive melanoma and demonstrated specificity for melanoma neoantigens. This phenomenon was observed in the presence of an extremely high tumour neoantigen load, which we confirmed to be associated with HLA class II positivity through the analysis of 116 melanoma specimens. Our data reveal the landscape of infiltrating CD4(+) T cells in melanoma and point to the presentation of HLA class II-restricted neoantigens and direct engagement of immunosuppressive CD4(+) T(Reg) cells as a mechanism of immune evasion that is favoured in HLA class II-positive melanoma.