Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy.
Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy.
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DOI：
10.1158/2159-8290.cd-15-0283
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发表时间：
2016-02
期刊：
影响因子：
28.2
通讯作者：
Hwu P
中科院分区：
文献类型：
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作者：
Peng W;Chen JQ;Liu C;Malu S;Creasy C;Tetzlaff MT;Xu C;McKenzie JA;Zhang C;Liang X;Williams LJ;Deng W;Chen G;Mbofung R;Lazar AJ;Torres-Cabala CA;Cooper ZA;Chen PL;Tieu TN;Spranger S;Yu X;Bernatchez C;Forget MA;Haymaker C;Amaria R;McQuade JL;Glitza IC;Cascone T;Li HS;Kwong LN;Heffernan TP;Hu J;Bassett RL Jr;Bosenberg MW;Woodman SE;Overwijk WW;Lizée G;Roszik J;Gajewski TF;Wargo JA;Gershenwald JE;Radvanyi L;Davies MA;Hwu P
T细胞介导的免疫疗法是有前途的癌症治疗方法。然而，大多数患者仍然对这些疗法没有反应。免疫抵抗的分子决定因素知之甚少。我们发现，在黑色素瘤的临床前模型中，肿瘤细胞中PTEN的缺失抑制了T细胞介导的肿瘤杀伤，并减少了T细胞向肿瘤中的运输。在患者中，PTEN丢失与肿瘤部位T细胞浸润减少、切除肿瘤成功T细胞扩增的可能性降低以及PD-1抑制剂治疗的不良结局相关。肿瘤细胞中的PTEN缺失增加了免疫抑制性细胞因子的表达，导致肿瘤中T细胞浸润减少，并抑制自噬，这减少了T细胞介导的细胞死亡。用选择性PI 3 K β抑制剂治疗改善了抗PD-1和抗CTLA 4抗体在鼠模型中的功效。总之，这些发现表明，PTEN缺失促进免疫抗性，并支持探索免疫疗法和PI 3 K-AKT通路抑制剂的组合的基本原理。
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-CTLA4 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.