TY - JOUR
T1 - Loss of PTEN promotes resistance to T cell–mediated immunotherapy
AU - Peng, Weiyi
AU - Chen, Jie Qing
AU - Liu, Chengwen
AU - Malu, Shruti
AU - Creasy, Caitlin
AU - Tetzlaff, Michael T.
AU - Xu, Chunyu
AU - McKenzie, Jodi A.
AU - Zhang, Chunlei
AU - Liang, Xiaoxuan
AU - Williams, Leila J.
AU - Deng, Wanleng
AU - Chen, Guo
AU - Mbofung, Rina
AU - Lazar, Alexander J.
AU - Torres-Cabala, Carlos A.
AU - Cooper, Zachary A.
AU - Chen, Pei Ling
AU - Tieu, Trang N.
AU - Spranger, Stefani
AU - Yu, Xiaoxing
AU - Bernatchez, Chantale
AU - Forget, Marie Andree
AU - Haymaker, Cara
AU - Amaria, Rodabe
AU - McQuade, Jennifer L.
AU - Glitza, Isabella C.
AU - Cascone, Tina
AU - Li, Haiyan S.
AU - Kwong, Lawrence N.
AU - Heffernan, Timothy P.
AU - Hu, Jianhua
AU - Bassett, Roland L.
AU - Bosenberg, Marcus W.
AU - Woodm An, Scott E.
AU - Overwijk, Willem W.
AU - Lizee, Gregory
AU - Roszik, Jason
AU - Gajewski, Thomas F.
AU - Wargo, Jennifer A.
AU - Gershenwald, Jeffrey E.
AU - Radvanyi, Laszlo
AU - Davies, Michael A.
AU - Hwu, Patrick
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2016/2
Y1 - 2016/2
N2 - 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 effi cacy of immunotherapy.
AB - 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 effi cacy of immunotherapy.
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UR - http://www.scopus.com/inward/citedby.url?scp=84957093642&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-15-0283
DO - 10.1158/2159-8290.CD-15-0283
M3 - Article
C2 - 26645196
AN - SCOPUS:84957093642
SN - 2159-8274
VL - 6
SP - 202
EP - 216
JO - Cancer discovery
JF - Cancer discovery
IS - 2
ER -