Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation.
Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation.
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DOI：
10.1016/j.ccell.2021.10.008
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发表时间：
2021-12-13
期刊：
影响因子：
50.3
通讯作者：
Coukos G
中科院分区：
文献类型：
--
作者：
Duraiswamy J;Turrini R;Minasyan A;Barras D;Crespo I;Grimm AJ;Casado J;Genolet R;Benedetti F;Wicky A;Ioannidou K;Castro W;Neal C;Moriot A;Renaud-Tissot S;Anstett V;Fahr N;Tanyi JL;Eiva MA;Jacobson CA;Montone KT;Westergaard MCW;Svane IM;Kandalaft LE;Delorenzi M;Sorger PK;Färkkilä A;Michielin O;Zoete V;Carmona SJ;Foukas PG;Powell DJ Jr;Rusakiewicz S;Doucey MA;Dangaj Laniti D;Coukos G
调节肿瘤浸润淋巴细胞（TIL）耗竭和对PD-1阻断的反应性的机制仍部分未知。在人类卵巢癌中，我们发现肿瘤特异性CD 8 + TIL在肿瘤胰岛中积累，在那里它们与抗原结合并上调PD-1，这抑制了它们的功能。然而，上皮内PD-1+ CD 8 + TIL可以是多功能的。PD-1+ TIL确实表现出连续的耗竭状态，具有可变水平的CD 28共刺激，其由上皮内肿瘤髓样小生境中的抗原呈递细胞（APC）提供。CD 28共刺激与耗尽的CD 8 + TIL的效应子适应性改善相关，并且是PD-1阻断后其活化所需的，这也需要肿瘤髓样APC。缺乏适当的原位CD 28共刺激的耗尽的TIL不能响应PD-1阻断，并且它们的响应可以通过局部CTLA-4阻断和经由CD 40 L的肿瘤APC刺激来挽救。Duraiswamy等人描述了浸润HGSOC的肿瘤特异性CD 8+淋巴细胞，并指出它们与原位上皮内髓样APC小生境密切相关。上皮内髓样APC小生境通过原位CD 28共刺激支持TIL，维持抗肿瘤免疫攻击并使对PD-1阻断的反应成为可能。
The mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TIL) and responsiveness to PD-1 blockade remain partly unknown. In human ovarian cancer we show that tumor-specific CD8+ TIL accumulate in tumor islets, where they engage antigen and upregulate PD-1, which restrains their functions. Intraepithelial PD-1+CD8+ TIL can be however polyfunctional. PD-1+ TIL indeed exhibit a continuum of exhaustion states, with variable levels of CD28 costimulation, which is provided by antigen-presenting cells (APC) in intraepithelial tumor myeloid niches. CD28 costimulation is associated with improved effector fitness of exhausted CD8+ TIL and is required for their activation upon PD-1 blockade, which also requires tumor myeloid APCs. Exhausted TIL lacking proper CD28 costimulation in situ fail to respond to PD-1 blockade, and their response may be rescued by local CTLA-4 blockade and tumor APC stimulation via CD40L. Duraiswamy et al. characterize tumor-specific CD8+ lymphocytes infiltrating HGSOC, and note their close association with intraepithelial myeloid APC niches in situ. Intraepithelial myeloid APC niches support TILs with CD28 costimulation in situ, sustaining antitumor immune attack and enabling response to PD-1 blockade.
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影响因子：
28.2
作者：
Chen PL;Roh W;Reuben A;Cooper ZA;Spencer CN;Prieto PA;Miller JP;Bassett RL;Gopalakrishnan V;Wani K;De Macedo MP;Austin-Breneman JL;Jiang H;Chang Q;Reddy SM;Chen WS;Tetzlaff MT;Broaddus RJ;Davies MA;Gershenwald JE;Haydu L;Lazar AJ;Patel SP;Hwu P;Hwu WJ;Diab A;Glitza IC;Woodman SE;Vence LM;Wistuba II;Amaria RN;Kwong LN;Prieto V;Davis RE;Ma W;Overwijk WW;Sharpe AH;Hu J;Futreal PA;Blando J;Sharma P;Allison JP;Chin L;Wargo JA
通讯作者：
Wargo JA
影响因子：
28.2
作者：
D'Angelo SP;Melchiori L;Merchant MS;Bernstein D;Glod J;Kaplan R;Grupp S;Tap WD;Chagin K;Binder GK;Basu S;Lowther DE;Wang R;Bath N;Tipping A;Betts G;Ramachandran I;Navenot JM;Zhang H;Wells DK;Van Winkle E;Kari G;Trivedi T;Holdich T;Pandite L;Amado R;Mackall CL
通讯作者：
Mackall CL
影响因子：
15.9
作者：
Baitsch, Lukas;Baumgaertner, Petra;Speiser, Daniel E.
通讯作者：
Speiser, Daniel E.
影响因子：
16.6
作者：
Bobisse S;Genolet R;Roberti A;Tanyi JL;Racle J;Stevenson BJ;Iseli C;Michel A;Le Bitoux MA;Guillaume P;Schmidt J;Bianchi V;Dangaj D;Fenwick C;Derré L;Xenarios I;Michielin O;Romero P;Monos DS;Zoete V;Gfeller D;Kandalaft LE;Coukos G;Harari A
通讯作者：
Harari A
影响因子：
64.5
作者：
Azizi E;Carr AJ;Plitas G;Cornish AE;Konopacki C;Prabhakaran S;Nainys J;Wu K;Kiseliovas V;Setty M;Choi K;Fromme RM;Dao P;McKenney PT;Wasti RC;Kadaveru K;Mazutis L;Rudensky AY;Pe'er D
通讯作者：
Pe'er D