PPT1 is a negative regulator of STING signaling in cancer cells and its inhibition reactivates immune surveillance in cold tumors
Abstract
Immunotherapy modalities have revolutionized cancer treatment for a number of metastatic and treatment-refractory tumor types. Still, many malignancies that lack T cell infiltration and are termed immunologically “cold” fail to respond to these modalities. One approach to increase tumor immunogenicity has been to induce stimulator of interferon gene (STING) and downstream interferon signaling that is often dysregulated in cold tumors. Despite some early success of STING agonists in preclinical cancer models, these approaches have not been successful in the clinic due to poor tumor penetrance and systemic toxicities. Here, we performed a genome-wide CRISPR screen to uncover therapeutic targets to activate STING expression in human tumors. We identified the lysosomal hydrolase Palmitoyl Protein Thioesterase1 (PPT1) as a negative regulator of STING highly expressed in cold ovarian and prostate tumors. Genetic or pharmacological PPT1 suppression increased STING protein stability and its downstream activation of interferon and inflammatory cytokine signaling to enhance T cell migration. Treatment of preclinical prostate and ovarian cancer models expressing low levels of STING with the small molecule PPT1 inhibitor GNS561 enhanced STING expression and activation, leading to infiltration and activation of cytotoxic T cells that turned these tumors “hot” and reduced tumor growth, fibrosis, and dissemination without toxicity. Further analysis demonstrated that PPT1 is associated with reduced STING expression, CD8 + T cell numbers, overall survival, and immunotherapy outcomes in ovarian and prostate cancer patients. Thus, PPT1 inhibition may be a promising approach to activate STING and potentiate the effects of immunotherapy in cold tumors.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (22)
Shreya R. Chowdhury
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School
Chaitanya N. Parikh
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School
Arshia N. Kaur
Department of Systems Biology, University of Massachusetts
Kelly D. DeMarco
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School
Hadiya K. Giwa
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School
Alok K. Mishra
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School
Katherine C. Murphy
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School
Lin Zhou
Boyang Ma
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School
Tianyi Ye
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School
Junhui Li
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School
Haibo Liu
Discovery & Development Sciences
Shi Bai
Department of Pathology, University of Massachusetts Medical Center
Calvin Johnson
Division of Hematology-Oncology, University of Massachusetts Chan Medical School
Karl Simin
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School
Jason R. Pitarresi
Division of Hematology-Oncology, University of Massachusetts Chan Medical School
Lihua Julie Zhu
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School
Emma V. Watson
Department of Systems Biology, University of Massachusetts
Michelle A. Kelliher
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School
Michael R. Green
Katherine A. Fitzgerald
Department of Medicine, University of Massachusetts Chan Medical School
Marcus Ruscetti
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School