Loss of PTEN Promotes Resistance to T Cell–Mediated Immunotherapy

Cancer Discovery - Tập 6 Số 2 - Trang 202-216 - 2016
Weiyi Peng1, Jie Qing Chen1, Chengwen Liu1, Shruti Malu1, Caitlin Creasy1, Michael T. Tetzlaff2,3, Chunyu Xu1, Jodi A. McKenzie1, Chunlei Zhang1, Xiaoxuan Liang1, Leila J. Williams1, Wanleng Deng1, Guo Chen1, Rina M. Mbofung1, Alexander J. Lazar2, Carlos A. Torres‐Cabala2, Zachary A. Cooper4,5, Pei-Ling Chen2, Trang N. Tieu6, Stefani Spranger7, Xiaoxing Yu1, Chantale Bernatchez1, Marie‐Andrée Forget1, Cara Haymaker1, Rodabe N. Amaria1, Jennifer L. McQuade8, Isabella C. Glitza1, Tina Cascone8, Haiyan S. Li9, Lawrence N. Kwong5, Timothy P. Heffernan6, Jianhua Hu10, Roland L. Bassett10, Marcus Bosenberg11, Scott E. Woodman1, Willem W. Overwijk1, Gregory Lizée1, Jason Roszik1,5, Thomas F. Gajewski7, Jennifer A. Wargo4,5, Jeffrey E. Gershenwald4, Laszlo G. Radvanyi1, Michael A. Davies1, Patrick Hwu1
11Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
22Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
33Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
44Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
55Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
66Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
77Department of Pathology, University of Chicago, Chicago, Illinois.
88Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
99Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
1010Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
1111Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.

Tóm tắt

Abstract T cell–mediated immunotherapies are promising cancer treatments. However, most patients still fail to respond to these therapies. The molecular determinants of immune resistance are poorly understood. We show that loss of PTEN in tumor cells in preclinical models of melanoma inhibits T cell–mediated tumor killing and decreases T-cell trafficking into tumors. In patients, PTEN loss correlates with decreased T-cell infiltration at tumor sites, reduced likelihood of successful T-cell expansion from resected tumors, and inferior outcomes with PD-1 inhibitor therapy. PTEN loss in tumor cells increased the expression of immunosuppressive cytokines, resulting in decreased T-cell infiltration in tumors, and inhibited autophagy, which decreased T cell–mediated cell death. Treatment with a selective PI3Kβ inhibitor improved the efficacy of both anti–PD-1 and anti–CTLA-4 antibodies in murine models. Together, these findings demonstrate that PTEN loss promotes immune resistance and support the rationale to explore combinations of immunotherapies and PI3K–AKT pathway inhibitors. Significance: This study adds to the growing evidence that oncogenic pathways in tumors can promote resistance to the antitumor immune response. As PTEN loss and PI3K–AKT pathway activation occur in multiple tumor types, the results support the rationale to further evaluate combinatorial strategies targeting the PI3K–AKT pathway to increase the efficacy of immunotherapy. Cancer Discov; 6(2); 202–16. ©2015 AACR. See related commentary by Rizvi and Chan, p. 128. This article is highlighted in the In This Issue feature, p. 109

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Cancer Discovery

Tập 6 Số 2

202-216

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