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Stupia, Simone; Heeke, Christina; Brüggemann, Alicia; Zaremba, Anne; Thier, Beatrice; Kretz, Julia; Sucker, Antje; Philip, Manuel; Zelinskyy, Gennadiy; Ferrone, Soldano; Roesch, Alexander; Horn, Susanne; Hadaschik, Eva; Schadendorf, Dirk; Trilling, Mirko; Dittmer, Ulf; Griewank, Klaus; Zhao, Fang; Paschen, Annette

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

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  • Medientyp: E-Artikel
  • Titel: HLA Class II Loss and JAK1/2 Deficiency Coevolve in Melanoma Leading to CD4 T-cell and IFNγ Cross-Resistance
  • Beteiligte: Stupia, Simone; Heeke, Christina; Brüggemann, Alicia; Zaremba, Anne; Thier, Beatrice; Kretz, Julia; Sucker, Antje; Philip, Manuel; Zelinskyy, Gennadiy; Ferrone, Soldano; Roesch, Alexander; Horn, Susanne; Hadaschik, Eva; Schadendorf, Dirk; Trilling, Mirko; Dittmer, Ulf; Griewank, Klaus; Zhao, Fang; Paschen, Annette
  • Erschienen: American Association for Cancer Research (AACR), 2023
  • Erschienen in: Clinical Cancer Research
  • Sprache: Englisch
  • DOI: 10.1158/1078-0432.ccr-23-0099
  • ISSN: 1078-0432; 1557-3265
  • Schlagwörter: Cancer Research ; Oncology
  • Entstehung:
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  • Beschreibung: <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats: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.</jats:p> </jats:sec> <jats:sec> <jats:title>Experimental Design:</jats:title> <jats: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).</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats: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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats: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.</jats:p> </jats:sec>