Integrin αvβ8 on T cells suppresses anti-tumor immunity in multiple models and is a promising target for tumor immunotherapy.
Integrin αvβ8 on T cells suppresses anti-tumor immunity in multiple models and is a promising target for tumor immunotherapy.
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T细胞上的整合素αvβ8在多种模型中抑制抗肿瘤免疫，并且是肿瘤免疫治疗的有希望的靶点。
DOI：
10.1016/j.celrep.2021.109309
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发表时间：
2021-07-06
期刊：
影响因子：
8.8
通讯作者：
Sheppard D
中科院分区：
文献类型：
--
作者：
Dodagatta-Marri E;Ma HY;Liang B;Li J;Meyer DS;Chen SY;Sun KH;Ren X;Zivak B;Rosenblum MD;Headley MB;Pinzas L;Reed NI;Del Cid JS;Hann BC;Yang S;Giddabasappa A;Noorbehesht K;Yang B;Dal Porto J;Tsukui T;Niessen K;Atakilit A;Akhurst RJ;Sheppard D
αvβ8整合素是转化生长因子β(β)的关键激活剂，可抑制抗肿瘤免疫。我们发现，在鳞状细胞癌、乳腺癌、结肠癌和前列腺癌的同基因模型中，有效的阻断αvβ8(ADWA-11)的单抗可导致生长抑制或完全消退，特别是当与其他免疫调节剂或放射治疗联合使用时。αvβ8在肿瘤中的CD 4+CD 2 5+T细胞中表达水平最高，特异性地从T细胞中删除β8在抑制肿瘤生长方面与ADW A-11一样有效。Adwa-11增加了肿瘤浸润性CD8+T细胞中一系列基因的表达，这些基因通常被转化生长因子-β抑制，并参与肿瘤细胞的杀伤，包括颗粒酶B和干扰素-γ。CD4+CD25+细胞可抑制肿瘤CD8T细胞的体外细胞毒作用，而ADWA-11可阻断这一抑制作用。这些发现巩固了αvβ8整合素作为癌症免疫治疗的一个有前途的靶点。转化生长因子-β抑制抗肿瘤免疫。Dodagatta-Marri，Ma等人。结果表明，转化生长因子β激活的整合素αvβ8在CD2 5+CD4+肿瘤T细胞上表达，并抑制CD8+T细胞的抗肿瘤免疫。阻断这种整合素可增强肿瘤细胞的杀伤力，并与多种免疫调节剂或放射治疗协同作用，诱导长期的抗肿瘤免疫。
αvβ8 integrin, a key activator of transforming growth factor β (TGF-β), inhibits anti-tumor immunity. We show that a potent blocking monoclonal antibody against αvβ8 (ADWA-11) causes growth suppression or complete regression in syngeneic models of squamous cell carcinoma, mammary cancer, colon cancer, and prostate cancer, especially when combined with other immunomodulators or radiotherapy. αvβ8 is expressed at the highest levels in CD4+CD25+ T cells in tumors, and specific deletion of β8 from T cells is as effective as ADWA-11 in suppressing tumor growth. ADWA-11 increases expression of a suite of genes in tumor-infiltrating CD8+ T cells normally inhibited by TGF-β and involved in tumor cell killing, including granzyme B and interferon-γ. The in vitro cytotoxic effect of tumor CD8 T cells is inhibited by CD4+CD25+ cells, and this suppressive effect is blocked by ADWA-11. These findings solidify αvβ8 integrin as a promising target for cancer immunotherapy. TGF-β suppresses anti-tumor immunity. Dodagatta-Marri, Ma et al. show that the TGF-β-activating integrin αvβ8 is expressed on CD25+CD4+ tumor T cells and suppresses anti-tumor immunity by CD8+ T cells. Blocking this integrin enhances tumor cell killing and synergizes with multiple immune modulators or radiotherapy to induce long-term anti-tumor immunity.
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影响因子：
2.9
作者：
ABE, M;HARPEL, JG;RIFKIN, DB
通讯作者：
RIFKIN, DB
影响因子：
10.1
作者：
Wu TC;Xu K;Banchereau R;Marches F;Yu CI;Martinek J;Anguiano E;Pedroza-Gonzalez A;Snipes GJ;O'Shaughnessy J;Nishimura S;Liu YJ;Pascual V;Banchereau J;Oh S;Palucka K
通讯作者：
Palucka K
影响因子：
64.8
作者：
Tauriello, Daniele V. F.;Palomo-Ponce, Sergio;Batlle, Eduard
通讯作者：
Batlle, Eduard
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1165/rcmb.2006-0238oc
发表时间：
2007-03-01
影响因子：
6.4
作者：
Su, George;Hodnett, Maki;Pittet, Jean-Francois
通讯作者：
Pittet, Jean-Francois