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

• DOI: 10.1158/1078-0432.c.6700316.v2
• Publication Date: 2023-08-01T08:47:51Z
• Authors: Simone Stupia; Christina Heeke; Alicia Brüggemann; Anne Zaremba; Beatrice Thier; Julia Kretz; Antje Sucker; Manuel Philip; Gennadiy Zelinskyy; Soldano Ferrone; Alexander Roesch; Susanne Horn; Eva Hadaschik; Dirk Schadendorf; Mirko Trilling; Ulf Dittmer; Klaus Griewank; Fang Zhao; Annette Paschen

<div>AbstractPurpose:<p>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.</p>Experimental Design:<p>Melanoma cells from longitudinal metastases were studied for constitutive and IFN-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).</p>Results:<p>Analysis of longitudinal samples revealed strong intermetastatic 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.</p>Conclusions:<p>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.</p></div>