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

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

doi:10.1158/1078-0432.CCR-23-0099

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

Clin Cancer Res. 2023 Aug 1;29(15):2894-2907. doi: 10.1158/1078-0432.CCR-23-0099.

Authors

Simone Stupia^#^{1

2}, Christina Heeke^#^{1

2}, Alicia Brüggemann^{1

2}, Anne Zaremba^{1

2}, Beatrice Thier^{1

2}, Julia Kretz^{1

2}, Antje Sucker^{1

2}, Manuel Philip^{1

2}, Gennadiy Zelinskyy³, Soldano Ferrone^#⁴, Alexander Roesch^{1

2}, Susanne Horn^{1

2

5}, Eva Hadaschik^{1

2}, Dirk Schadendorf^{1

2}, Mirko Trilling³, Ulf Dittmer³, Klaus Griewank^{1

2}, Fang Zhao^#^{1

2}, Annette Paschen^#^{1

2}

Affiliations

¹ Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
² German Consortium for Translational Cancer Research (DKTK), Partner Site Essen/Düsseldorf, Germany.
³ Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
⁴ Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
⁵ Rudolf-Schönheimer-Institute of Biochemistry, University Leipzig, Leipzig, Germany.

^# Contributed equally.

PMID: 37199727
DOI: 10.1158/1078-0432.CCR-23-0099

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 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).

Results: 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.

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.

Abstract

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