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JCI Insight. 2017 Sep 21;2(18). pii: 93265. doi: 10.1172/jci.insight.93265. eCollection 2017 Sep 21.

Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity.

Author information

1
Department of Pediatrics and Microbiology/Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
2
Diabetes Center, UCSF, San Francisco, California, USA.
3
Center for Gastrointestinal Biology and Disease.
4
Department of Pathology and Laboratory Medicine, School of Medicine, and.
5
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
6
Division of Hematology/Oncology, Department of Medicine, UCSF, San Francisco, California, USA.
7
Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
8
Melanoma Committee, ECOG-ACRIN Cancer Research Group, and.
9
Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
10
Division of Hematology/Oncology, Department of Medicine, School of Medicine, and.
11
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Abstract

Blockade of immune checkpoint proteins (e.g., CTLA-4, PD-1) improves overall survival in advanced melanoma; however, therapeutic benefit is limited to only a subset of patients. Because checkpoint blockade acts by "removing the brakes" on effector T cells, the efficacy of checkpoint blockade may be constrained by the limited pool of melanoma-reactive T cells in the periphery. In the thymus, autoimmune regulator (Aire) promotes deletion of T cells reactive against self-antigens that are also expressed by tumors. Thus, while protecting against autoimmunity, Aire also limits the generation of melanoma-reactive T cells. Here, we show that Aire deficiency in mice expands the pool of CD4+ T cells capable of melanoma cell eradication and has additive effects with anti-CTLA-4 antibody in slowing melanoma tumor growth and increasing survival. Moreover, pharmacologic blockade of central T cell tolerance and peripheral checkpoint blockade in combination enhanced antimelanoma immunity in a synergistic manner. In melanoma patients treated with anti-CTLA-4 antibody, clinical response to therapy was associated with a human Aire polymorphism. Together, these findings suggest that Aire-mediated central tolerance constrains the efficacy of peripheral checkpoint inhibition and point to simultaneous blockade of Aire and checkpoint inhibitors as a novel strategy to enhance antimelanoma immunity.

KEYWORDS:

Cancer immunotherapy; Cellular immune response; Immunology; Melanoma

PMID:
28931755
PMCID:
PMC5621898
DOI:
10.1172/jci.insight.93265
[Indexed for MEDLINE]
Free PMC Article

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