Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells.
Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells.
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DOI：
10.1038/nature20554
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发表时间：
2016-11-17
期刊：
影响因子：
64.8
通讯作者：
Merghoub T
中科院分区：
文献类型：
--
作者：
De Henau O;Rausch M;Winkler D;Campesato LF;Liu C;Cymerman DH;Budhu S;Ghosh A;Pink M;Tchaicha J;Douglas M;Tibbitts T;Sharma S;Proctor J;Kosmider N;White K;Stern H;Soglia J;Adams J;Palombella VJ;McGovern K;Kutok JL;Wolchok JD;Merghoub T
最近的临床试验表明，免疫疗法可以通过解除免疫系统的抑制来控制癌症。免疫检查点阻断（ICB）抗体，如抗细胞毒性t淋巴细胞相关蛋白4（抗ctla -4）或抗程序性细胞死亡蛋白1/抗程序性死亡配体1（抗pd -1/抗pd - l1）已在各种癌症中显示出持久的临床反应。尽管这些新的免疫疗法对癌症治疗有重大影响，但肿瘤中存在多种免疫抵抗机制。在关键机制中，髓系细胞在限制有效的肿瘤免疫中起主要作用。越来越多的证据表明，免疫抑制髓细胞的高浸润与预后不良和ICB抵抗相关。这些观察结果表明，需要一种精确的医学方法，根据肿瘤免疫景观量身定制免疫治疗组合的设计，以克服这种耐药机制。在此，我们采用临床前模型系统，并表明对ICB的抗性是由浸润性髓细胞的抑制活性直接介导的。此外，选择性药物靶向在髓细胞中高度表达的磷酸肌肽3-激酶(PI3K-γ) γ亚型，可以恢复对ICB的敏感性。我们证明，使用一种选择性抑制剂靶向PI3K -γ，目前正在1期临床试验中进行评估（NCT02637531），可以重塑肿瘤免疫微环境，促进细胞毒性T细胞介导的肿瘤消退，而无需直接靶向癌细胞。我们的研究结果为使用选择性小分子PI3K-γ抑制剂（如IPI-549）的新联合策略提供了机会，以克服肿瘤中高水平抑制性骨髓细胞浸润患者对ICB的耐药性。
Recent clinical trials using immunotherapy demonstrate its potential to control cancer by disinhibiting the immune system. Immune checkpoint blocking (ICB) antibodies such as anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) or anti-Programmed cell death protein 1/anti-Programmed death-ligand 1 (anti-PD-1/anti-PD-L1) have demonstrated durable clinical responses in various cancers. Although these new immunotherapies have significant impact on cancer treatment, multiple mechanisms of immune resistance exist in tumors. Among the key mechanisms, myeloid cells play a major role in limiting effective tumor immunity. Growing evidence suggests that high infiltration of immune-suppressive myeloid cells correlates with poor prognosis and ICB resistance. These observations suggest a need for a precision medicine approach where the design of the immunotherapeutic combinations are tailored based on tumor immune landscape to overcome such resistance mechanisms. Herein we employ a preclinical model system and show that resistance to ICB is directly mediated by the suppressive activity of infiltrating myeloid cells in various tumors. Furthermore, selective pharmacologic targeting of the gamma isoform of phosphoinositide 3-kinase (PI3K-γ), highly expressed in myeloid cells, restores sensitivity to ICB. We demonstrate that targeting PI3K–γ, with a selective inhibitor, currently being evaluated in a phase 1 clinical trial (NCT02637531), can reshape the tumor immune microenvironment and promote cytotoxic T cell-mediated tumor regression without targeting cancer cells directly. Our results introduce opportunities for new combination strategies using a selective small molecule PI3K-γ inhibitor, such as IPI-549, to overcome resistance to ICB in patients with high levels of suppressive myeloid cell infiltration in tumors.
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单核细胞CCR2（+）髓样衍生的抑制细胞通过将活化的CD8 T细胞浸润限制在肿瘤微环境中，从而促进免疫逃逸。
影响因子：
11.2
作者：
Lesokhin AM;Hohl TM;Kitano S;Cortez C;Hirschhorn-Cymerman D;Avogadri F;Rizzuto GA;Lazarus JJ;Pamer EG;Houghton AN;Merghoub T;Wolchok JD
通讯作者：
Wolchok JD
DOI：
10.1056/nejmoa1504030
发表时间：
2015-07-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Larkin J;Chiarion-Sileni V;Gonzalez R;Grob JJ;Cowey CL;Lao CD;Schadendorf D;Dummer R;Smylie M;Rutkowski P;Ferrucci PF;Hill A;Wagstaff J;Carlino MS;Haanen JB;Maio M;Marquez-Rodas I;McArthur GA;Ascierto PA;Long GV;Callahan MK;Postow MA;Grossmann K;Sznol M;Dreno B;Bastholt L;Yang A;Rollin LM;Horak C;Hodi FS;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
11.2
作者：
Movahedi, Kiavash;Laoui, Damya;Van Ginderachter, Jo A.
通讯作者：
Van Ginderachter, Jo A.
影响因子：
50.3
作者：
Schmid MC;Avraamides CJ;Dippold HC;Franco I;Foubert P;Ellies LG;Acevedo LM;Manglicmot JR;Song X;Wrasidlo W;Blair SL;Ginsberg MH;Cheresh DA;Hirsch E;Field SJ;Varner JA
通讯作者：
Varner JA
影响因子：
4.2
作者：
Evans, Catherine A.;Liu, Tao;Castro, Alfredo C.
通讯作者：
Castro, Alfredo C.