Funding
NCI
MDACC Melanoma SPORE, MDACC Cancer Center Support
by philanthropic contributions to the MDACC Melanoma Moon Shots Program; a Melanoma Research Alliance Team Science Award; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the Aim at Melanoma Foundation, Miriam and Jim Mulva research funds; Jurgen Sager and Transocean Melanoma Research Fund; the El Paso Foundation for Melanoma Research; the Gillson Logenbaugh Foundation, and the Cancer Prevention and Research Institute of Texas
John G. and Marie Stella Kenedy Memorial Foundation
ARTICLE 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
