Small-molecule PTPN2 Inhibitors Sensitize Resistant Melanoma to Anti-PD-1 Immunotherapy

Author:

Zhu Zhouting1ORCID,Tang Rachel1ORCID,Huff Sarah1ORCID,Kummetha Indrasena Reddy1ORCID,Wang Lingling1ORCID,Li Na1ORCID,Rana Tariq M.12ORCID

Affiliation:

1. 1Division of Genetics, Department of Pediatrics, Program in Immunology, Institute for Genomic Medicine, University of California San Diego, La Jolla, California.

2. 2San Diego Center for Precision Immunotherapy, Moores Cancer Center, University of California San Diego, La Jolla, California.

Abstract

Although immune checkpoint inhibitors targeting T-cell immunoregulatory proteins have revolutionized cancer treatment, they are effective only in a limited number of patients, and new strategies are needed to enhance tumor responses to immunotherapies. Deletion of protein tyrosine phosphatase non-receptor type 2 (Ptpn2), a regulator of growth factor and cytokine signaling pathways, has been shown to sensitize murine B16F10 melanoma cells to IFNγ and anti-PD-1 immunotherapy. Here, we investigated the potential therapeutic utility of small-molecule PTPN2 inhibitors. Ten inhibitors were synthesized on the basis of in silico modeling and structure-based design and functionally tested in vitro and in vivo. We show that the inhibitors had little effect on B16F10 cells alone, but effectively sensitized the tumor cells to IFNγ treatment in vitro and to anti-PD-1 therapy in vivo. Under both conditions, Ptpn2 inhibitor cotreatment suppressed B16F10 cell growth and enhanced Stat1 phosphorylation and expression of IFNγ response genes. In vivo, PTPN2 inhibitor cotreatment significantly reduced melanoma and colorectal tumor growth and enhanced mouse survival compared with anti-PD-1 treatment alone, and this was accompanied by increased tumor infiltration by granzyme B+ CD8+ T cells. Similar results were obtained with representative murine and human colon cancer and lung cancer cell lines. Collectively, these results demonstrate that small-molecule inhibitors of PTPN2 may have clinical utility as sensitizing agents for immunotherapy-resistant cancers. Significance: To enhance the effectiveness of immunotherapies in resistant or nonresponsive cancers, it is important to develop inhibitors of enzymes that negatively influence the outcome of treatments. We have designed and evaluated small-molecule inhibitors of PTPN2 demonstrating that these compounds may have clinical utility as sensitizing agents for immunotherapy-resistant cancers.

Funder

HHS | NIH | National Cancer Institute

Publisher

American Association for Cancer Research (AACR)

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