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Immunity. 2019 Feb 19;50(2):477-492.e8. doi: 10.1016/j.immuni.2019.01.006. Epub 2019 Feb 5.

Clonal Deletion of Tumor-Specific T Cells by Interferon-γ Confers Therapeutic Resistance to Combination Immune Checkpoint Blockade.

Author information

1
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.
2
Department of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
3
AbbVie Bioresearch Center, 100 Research Drive, Worcester, MA 01605, USA.
4
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
5
Department of Hematopathology, School of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
6
Girihlet, 355 30th Street, Oakland, CA 94609, USA.
7
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.

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.

KEYWORDS:

IFN-γ; activation-induced cell death; anti-CTLA-4; anti-PD-1; cancer; immunotherapy

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