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Tumor heterogeneity and clonal cooperation influence the immune selection of IFN-γ-signaling mutant cancer cells.
Williams, Jason B; Li, Shuyin; Higgs, Emily F; Cabanov, Alexandra; Wang, Xiaozhong; Huang, Haochu; Gajewski, Thomas F.
Afiliação
  • Williams JB; Department of Pathology, The University of Chicago, Chicago, IL, 60637, United States.
  • Li S; Department of Pathology, The University of Chicago, Chicago, IL, 60637, United States.
  • Higgs EF; Department of Pathology, The University of Chicago, Chicago, IL, 60637, United States.
  • Cabanov A; Department of Pathology, The University of Chicago, Chicago, IL, 60637, United States.
  • Wang X; Department of Molecular Biosciences, Northwestern University, Evanston, IL, 60208, United States.
  • Huang H; Department of Pathology, The University of Chicago, Chicago, IL, 60637, United States.
  • Gajewski TF; Department of Pathology, The University of Chicago, Chicago, IL, 60637, United States. tgajewsk@medicine.bsd.uchicago.edu.
Nat Commun ; 11(1): 602, 2020 01 30.
Article em En | MEDLINE | ID: mdl-32001684
PD-1/PD-L1 blockade can promote robust tumor regression yet secondary resistance often occurs as immune selective pressure drives outgrowth of resistant tumor clones. Here using a genome-wide CRISPR screen in B16.SIY melanoma cells, we confirm Ifngr2 and Jak1 as important genes conferring sensitivity to T cell-mediated killing in vitro. However, when implanted into mice, these Ifngr2- and Jak1-deficient tumors paradoxically are better controlled immunologically. This phenotype maps to defective PD-L1 upregulation on mutant tumor cells, which improves anti-tumor efficacy of CD8+ T cells. To reconcile these observations with clinical reports of anti-PD-1 resistance linked to emergence of IFN-γ signaling mutants, we show that when mixed with wild-type tumor cells, IFN-γ-insensitive tumor cells indeed grow out, which depends upon PD-L1 expression by wild-type cells. Our results illustrate the complexity of functions for IFN-γ in anti-tumor immunity and demonstrate that intratumor heterogeneity and clonal cooperation can contribute to immunotherapy resistance.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Interferon gama / Heterogeneidade Genética / Mutação / Neoplasias Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Interferon gama / Heterogeneidade Genética / Mutação / Neoplasias Idioma: En Ano de publicação: 2020 Tipo de documento: Article