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IL36 Cooperates With Anti-CTLA-4 mAbs to Facilitate Antitumor Immune Responses

Authors
  • Qu, Qiuxia1
  • Zhai, Zhiwei1
  • Xu, Jieni2
  • Li, Song2
  • Chen, Cheng1
  • Lu, Binfeng1, 3
  • 1 Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA , (United States)
  • 2 Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA , (United States)
  • 3 UPMC Hillman Cancer Center, Pittsburgh, PA , (United States)
Type
Published Article
Journal
Frontiers in Immunology
Publisher
Frontiers Media SA
Publication Date
Apr 15, 2020
Volume
11
Identifiers
DOI: 10.3389/fimmu.2020.00634
PMID: 32351508
PMCID: PMC7174717
Source
PubMed Central
Keywords
License
Unknown

Abstract

Despite the great impact on long-term survival of some cancer patients, the immune checkpoint blockade (ICB) therapy is limited by its low response rates for most cancers. There is a pressing need for novel combination immunotherapies that overcome the resistance to current ICB therapies. Cytokines play a pivotal role in tumor immunotherapy by helping initiating and driving antitumor immune responses. Here, we demonstrated that, besides conventional CD4+ and CD8+ T cells, IL36 surprisingly increased the number of tumor-infiltrating regulatory T (Treg) cells in vivo and enhanced proliferation of Tregs in vitro . Administration of CTLA-4 monoclonal antibodies (mAbs) strongly enhanced IL36-stimulated antitumor activities through depletion of Tregs. In addition, a cancer gene therapy using the IL36-loaded nanoparticles in combination with CTLA-4 mAbs additively reduced lung metastasis of breast tumor cells. We further showed that the combined therapy of CTLA-4 mAbs and IL36 led to an increase in proliferation and IFN-γ production by CD4+ and CD8+ T cells when compared to single therapy with CTLA-4 mAbs or IL36. Collectively, our findings demonstrated a new combination therapy that could improve the clinical response to ICB immunotherapy for cancer.

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