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Clonal Deletion of Tumor-Specific T Cells by Interferon-γ Confers Therapeutic Resistance to Combination Immune Checkpoint Blockade.
Pai, Chien-Chun Steven; Huang, John T; Lu, Xiaoqing; Simons, Donald M; Park, Chanhyuk; Chang, Anthony; Tamaki, Whitney; Liu, Eric; Roybal, Kole T; Seagal, Jane; Chen, Mingyi; Hagihara, Katsunobu; Wei, Xiao X; DuPage, Michel; Kwek, Serena S; Oh, David Y; Daud, Adil; Tsai, Katy K; Wu, Clint; Zhang, Li; Fasso, Marcella; Sachidanandam, Ravi; Jayaprakash, Anitha; Lin, Ingrid; Casbon, Amy-Jo; Kinsbury, Gillian A; Fong, Lawrence.
Affiliation
  • Pai CS; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Huang JT; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Lu X; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA.
  • Simons DM; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA.
  • Park C; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Chang A; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Tamaki W; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Liu E; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Roybal KT; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Seagal J; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA.
  • Chen M; Department of Hematopathology, School of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • Hagihara K; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Wei XX; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • DuPage M; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Kwek SS; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Oh DY; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Daud A; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Tsai KK; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Wu C; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Zhang L; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Fasso M; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Sachidanandam R; Girihlet, 355 30th Street, Oakland, CA 94609, USA.
  • Jayaprakash A; Girihlet, 355 30th Street, Oakland, CA 94609, USA.
  • Lin I; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Casbon AJ; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Kinsbury GA; AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA.
  • Fong L; Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: lawrence.fong@ucsf.edu.
Immunity ; 50(2): 477-492.e8, 2019 02 19.
Article in En | MEDLINE | ID: mdl-30737146
ABSTRACT
Resistance to checkpoint-blockade treatments is a challenge in the clinic. We found that although treatment with combined anti-CTLA-4 and anti-PD-1 improved control of established tumors, this combination compromised anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. Activated tumor-specific T cells expressed higher amounts of interferon-γ (IFN-γ) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor-specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower-frequency clonotypes. Additionally, combination therapy induced higher IFN-γ production in the LTB state than in the high tumor burden (HTB) state on a per-cell basis, reflecting a less exhausted immune status in the LTB state. Thus, elevated IFN-γ secretion in the LTB state contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade, highlighting the importance of achieving the optimal magnitude of immune stimulation for successful combination immunotherapy strategies.
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Full text: 1 Database: MEDLINE Main subject: T-Lymphocytes / Interferon-gamma / Drug Resistance, Neoplasm / CTLA-4 Antigen / Programmed Cell Death 1 Receptor / Antibodies, Monoclonal / Neoplasms, Experimental Limits: Animals / Humans / Male Language: En Journal: Immunity Journal subject: ALERGIA E IMUNOLOGIA Year: 2019 Type: Article Affiliation country: United States
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Full text: 1 Database: MEDLINE Main subject: T-Lymphocytes / Interferon-gamma / Drug Resistance, Neoplasm / CTLA-4 Antigen / Programmed Cell Death 1 Receptor / Antibodies, Monoclonal / Neoplasms, Experimental Limits: Animals / Humans / Male Language: En Journal: Immunity Journal subject: ALERGIA E IMUNOLOGIA Year: 2019 Type: Article Affiliation country: United States