American Association for Cancer Research
ccr-23-0099_supplementary_figure_s5_suppfs5.pdf (348.54 kB)

Supplementary Figure S5 from HLA Class II Loss and JAK1/2 Deficiency Coevolve in Melanoma Leading to CD4 T-cell and IFNγ Cross-Resistance

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journal contribution
posted on 2023-06-16, 15:00 authored by 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

No chromosomal alterations in the MHC region of HLA-II-loss JAK1/2 mutant melanoma cells



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. 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). 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. 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.

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