Hydroxychloroquine can impair tumor response to anti-PD1 in subcutaneous mouse models

Simon Wabitsch; John C McVey; Chi Ma; Benjamin Ruf; Olena Kamenyeva; Justin D McCallen; Laurence P Diggs; Bernd Heinrich; Tim F Greten

doi:10.1016/j.isci.2020.101990

Hydroxychloroquine can impair tumor response to anti-PD1 in subcutaneous mouse models

iScience. 2020 Dec 26;24(1):101990. doi: 10.1016/j.isci.2020.101990. eCollection 2021 Jan 22.

Authors

Simon Wabitsch¹, John C McVey^{1

2}, Chi Ma¹, Benjamin Ruf¹, Olena Kamenyeva³, Justin D McCallen¹, Laurence P Diggs¹, Bernd Heinrich¹, Tim F Greten¹

Affiliations

¹ Gastrointestinal Malignancy Section, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, 10/3B43, Bethesda, MD 20892, USA.
² Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA.
³ Biological Imaging Section, Research Technology Branch, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.

Abstract

Hydroxychloroquine (HCQ) is a well-known anti-inflammatory drug but is also known as an anti-inflammatory drug. Here, we evaluate the influence of HCQ treatment on the effect of anti-PD1 tumor immunotherapy. Anti-PD1 therapy-sensitive tumor lines MC38, CT26, and RIL-175 were used to investigate the impact of HCQ on anti-PD1 therapy efficacy. In vitro assays demonstrated that HCQ directly inhibited tumor cell growth in all the tested tumor cell lines. HCQ treatment impaired both antigen-specific and nonspecific T-cell production of TNFα and IFNγ in vitro and in vivo. Importantly, in all the three tumor models, HCQ treatment significantly impaired the response to anti-PD1 treatment, accompanying diminished in vivo T-cell activation and reduced tumor-infiltrating, antigen-specific CD8⁺ T cells. This study shows that HCQ treatment can result in immunotherapy failure due to its immunosuppressive effects that offset both increased MHC-I expression by tumor cell and direct cytotoxicity.

Keywords: Cancer; Immunology.