HLA Class II Loss and JAK1/2 Deficiency Coevolve in Melanoma Leading to CD4 T-cell and IFNγ Cross-Resistance

Abstract

Purpose: Recent studies have demonstrated HLA class II (HLA-II)-dependent killing of melanoma cells by cytotoxic CD4 T cells. We investigated evolution of HLA-II-loss tumors that escape cytotoxic CD4 T cell activity and contribute to immunotherapy resistance. Experimental Design: Melanoma cells from longitudinal metastases were studied for constitutive and interferon-inducible HLA-II expression, sensitivity towards autologous CD4 T cells, and immune evasion by HLA-II loss. Clinical significance of HLA-II-low tumors was determined by analysis of transcriptomic data sets from patients with immune checkpoint blockade (ICB). Results: Analysis of longitudinal samples revealed strong inter-metastatic heterogeneity in melanoma cell-intrinsic HLA-II expression and subclonal HLA-II loss. Tumor cells from early lesions either constitutively expressed HLA-II, sensitizing to cytotoxic CD4 T cells, or induced HLA-II and gained CD4 T cell sensitivity in the presence of IFNγ. In contrast, late outgrowing subclones displayed a stable CD4 T cell-resistant HLA-II-loss phenotype. These cells lacked not only constitutive but also IFNγ-inducible HLA-II due to JAK1/2-STAT1 pathway inactivation. Coevolution of JAK1/2 deficiency and HLA-II loss established melanoma cross-resistance to IFNγ and CD4 T cells, as detected in distinct stage IV metastases. In line with their immune-evasive phenotype, HLA-II-low melanomas showed reduced CD4 T cell infiltrates and correlated with disease progression under ICB. Conclusions: Our study links melanoma resistance to CD4 T cells, IFNγ, and ICB at the level of HLA-II, highlighting the significance of tumor cell-intrinsic HLA-II antigen presentation in disease control and calling for strategies to overcome its downregulation for improvement of patient outcome

Deciphering CD4+ T cell‐mediated responses against cancer

“…49 However, a later study found that melanoma cells prior to ICB had IFN-γ-inducible or constitutively expressed HLA class II, and these cells were sensitive to CD4 + T cellmediated killing in vitro. 50 Interestingly, after ICB treatments, the expression of HLA class II in these melanoma cells was lost, together with the loss of JAK/STAT signaling components. These results suggested the potential role of CD4 + T cells in the immune surveillance against melanoma cells and an important mechanism of immune resistance in melanoma cells against CD4 + T cells following ICB.…”