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Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy.


ABSTRACT: UNLABELLED: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 PI3K? 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.

SUBMITTER: Peng W 

PROVIDER: S-EPMC4744499 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy.

Peng Weiyi W   Chen Jie Qing JQ   Liu Chengwen C   Malu Shruti S   Creasy Caitlin C   Tetzlaff Michael T MT   Xu Chunyu C   McKenzie Jodi A JA   Zhang Chunlei C   Liang Xiaoxuan X   Williams Leila J LJ   Deng Wanleng W   Chen Guo G   Mbofung Rina R   Lazar Alexander J AJ   Torres-Cabala Carlos A CA   Cooper Zachary A ZA   Chen Pei-Ling PL   Tieu Trang N TN   Spranger Stefani S   Yu Xiaoxing X   Bernatchez Chantale C   Forget Marie-Andree MA   Haymaker Cara C   Amaria Rodabe R   McQuade Jennifer L JL   Glitza Isabella C IC   Cascone Tina T   Li Haiyan S HS   Kwong Lawrence N LN   Heffernan Timothy P TP   Hu Jianhua J   Bassett Roland L RL   Bosenberg Marcus W MW   Woodman Scott E SE   Overwijk Willem W WW   Lizée Gregory G   Roszik Jason J   Gajewski Thomas F TF   Wargo Jennifer A JA   Gershenwald Jeffrey E JE   Radvanyi Laszlo L   Davies Michael A MA   Hwu Patrick P  

Cancer discovery 20151208 2


<h4>Unlabelled</h4>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-  ...[more]

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