Platelets subvert T cell immunity against cancer via GARP-TGFβ axis.
Platelets subvert T cell immunity against cancer via GARP-TGFβ axis.
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DOI：
10.1126/sciimmunol.aai7911
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发表时间：
2017-05-05
影响因子：
24.8
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Rachidi S;Metelli A;Riesenberg B;Wu BX;Nelson MH;Wallace C;Paulos CM;Rubinstein MP;Garrett-Mayer E;Hennig M;Bearden DW;Yang Y;Liu B;Li Z
长期以来，癌症相关的血小板增多症与不良的临床结局有关，但其潜在机制仍是谜。我们假设血小板通过抑制宿主免疫力而促进恶性肿瘤和对治疗的抵抗。我们在此表明，血小板的遗传靶向显著增强癌症的过继性T细胞治疗。无偏生化和结构生物学方法确定转化生长因子β（TGFβ）和乳酸盐是主要的血小板源性可溶性因子，可消除CD 4+和CD 8 + T细胞功能。此外，我们发现血小板是全身性以及肿瘤微环境中功能性TGFβ的主要来源，其通过组成性表达TGFβ对接受体糖蛋白A重复占优势（GARP）而不是分泌TGFβ本身。事实上，GARP编码基因Lrrc 32的血小板特异性缺失减弱了肿瘤部位的TGFβ活性，并增强了对黑色素瘤和结肠癌的保护性免疫。最后，我们发现，癌症的T细胞治疗可以通过与容易获得的抗血小板剂同时治疗而得到实质性改善。我们得出结论，血小板通过GARP-TGFβ轴限制T细胞免疫，并建议将免疫疗法和血小板抑制剂组合作为对抗癌症的治疗策略。
Cancer-associated thrombocytosis has long been linked to poor clinical outcome, but the underlying mechanism is enigmatic. We hypothesized that platelets promote malignancy and resistance to therapy by dampening host immunity. We herein show that genetic targeting of platelets significantly enhances adoptive T cell therapy of cancer. An unbiased biochemical and structural biology approach established transforming growth factor β (TGFβ) and lactate as the major platelet-derived soluble factors to obliterate CD4+ and CD8+ T cell functions. Moreover, we found that platelets are the dominant source of functional TGFβ systemically as well as in the tumor microenvironment through constitutive expression of TGFβ-docking receptor Glycoprotein A Repetitions Predominant (GARP) rather than secretion of TGFβ per se. Indeed, platelet-specific deletion of GARP-encoding gene Lrrc32 blunted TGFβ activity at the tumor site and potentiated protective immunity against both melanoma and colon cancer. Finally, we found that T cell therapy of cancer can be substantially improved by concurrent treatment with readily available anti-platelet agents. We conclude that platelets constrain T cell immunity though a GARP-TGFβ axis and suggest a combination of immunotherapy and platelet inhibitors as a therapeutic strategy against cancer.
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影响因子：
10.1
作者：
Johnson CB;Riesenberg BP;May BR;Gilreath SC;Li G;Staveley-O'Carroll KF;Garrett-Mayer E;Mehrotra S;Cole DJ;Rubinstein MP
通讯作者：
Rubinstein MP
DOI：
10.1073/pnas.94.2.663
发表时间：
1997-01-21
影响因子：
11.1
作者：
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通讯作者：
Rafii, S
影响因子：
17.1
作者：
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影响因子：
17.1
作者：
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通讯作者：
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影响因子：
50.3
作者：
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通讯作者：
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