Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy.
Complement downregulation promotes an inflammatory signature that renders colorectal cancer susceptible to immunotherapy.
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DOI：
10.1136/jitc-2022-004717
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发表时间：
2022-09
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
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作者：
The role of inflammatory immune responses in colorectal cancer (CRC) development and response to therapy is a matter of intense debate. While inflammation is a known driver of CRC, inflammatory immune infiltrates are a positive prognostic factor in CRC and predispose to response to immune checkpoint blockade (ICB) therapy. Unfortunately, over 85% of CRC cases are primarily unresponsive to ICB due to the absence of an immune infiltrate, and even the cases that show an initial immune infiltration can become refractory to ICB. The identification of therapy supportive immune responses in the field has been partially hindered by the sparsity of suitable mouse models to recapitulate the human disease. In this study, we aimed to understand how the dysregulation of the complement anaphylatoxin C3a receptor (C3aR), observed in subsets of patients with CRC, affects the immune responses, the development of CRC, and response to ICB therapy. We use a comprehensive approach encompassing analysis of publicly available human CRC datasets, inflammation-driven and newly generated spontaneous mouse models of CRC, and multiplatform high-dimensional analysis of immune responses using microbiota sequencing, RNA sequencing, and mass cytometry. We found that patients’ regulation of the complement C3aR is associated with epigenetic modifications. Specifically, downregulation of C3ar1 in human CRC promotes a tumor microenvironment characterized by the accumulation of innate and adaptive immune cells that support antitumor immunity. In addition, in vivo studies in our newly generated mouse model revealed that the lack of C3a in the colon activates a microbiota-mediated proinflammatory program which promotes the development of tumors with an immune signature that renders them responsive to the ICB therapy. Our findings reveal that C3aR may act as a previously unrecognized checkpoint to enhance antitumor immunity in CRC. C3aR can thus be exploited to overcome ICB resistance in a larger group of patients with CRC.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
56.9
作者：
Del Poggetto, Edoardo;Ho, I-Lin;Balestrieri, Chiara;Yen, Er-Yen;Zhang, Shaojun;Citron, Francesca;Shah, Rutvi;Corti, Denise;Diaferia, Giuseppe R.;Li, Chieh-Yuan;Loponte, Sara;Carbone, Federica;Hayakawa, Yoku;Valenti, Giovanni;Jiang, Shan;Sapio, Luigi;Jiang, Hong;Dey, Prasenjit;Gao, Sisi;Deem, Angela K.;Rose-John, Stefan;Yao, Wantong;Ying, Haoqiang;Rhim, Andrew D.;Genovese, Giannicola;Heffernan, Timothy P.;Maitra, Anirban;Wang, Timothy C.;Wang, Linghua;Draetta, Giulio F.;Carugo, Alessandro;Natoli, Gioacchino;Viale, Andrea
通讯作者：
Viale, Andrea
影响因子：
28.2
作者：
Grasso CS;Giannakis M;Wells DK;Hamada T;Mu XJ;Quist M;Nowak JA;Nishihara R;Qian ZR;Inamura K;Morikawa T;Nosho K;Abril-Rodriguez G;Connolly C;Escuin-Ordinas H;Geybels MS;Grady WM;Hsu L;Hu-Lieskovan S;Huyghe JR;Kim YJ;Krystofinski P;Leiserson MDM;Montoya DJ;Nadel BB;Pellegrini M;Pritchard CC;Puig-Saus C;Quist EH;Raphael BJ;Salipante SJ;Shin DS;Shinbrot E;Shirts B;Shukla S;Stanford JL;Sun W;Tsoi J;Upfill-Brown A;Wheeler DA;Wu CJ;Yu M;Zaidi SH;Zaretsky JM;Gabriel SB;Lander ES;Garraway LA;Hudson TJ;Fuchs CS;Ribas A;Ogino S;Peters U
通讯作者：
Peters U
肿瘤浸润 T 辅助细胞 17 在人类结直肠癌中的双重作用。
影响因子：
24.5
作者：
Amicarella F;Muraro MG;Hirt C;Cremonesi E;Padovan E;Mele V;Governa V;Han J;Huber X;Droeser RA;Zuber M;Adamina M;Bolli M;Rosso R;Lugli A;Zlobec I;Terracciano L;Tornillo L;Zajac P;Eppenberger-Castori S;Trapani F;Oertli D;Iezzi G
通讯作者：
Iezzi G
T 辅助细胞 1 免疫需要 CD4⁺ T 细胞中补体驱动的 NLRP3 炎性体活性。
DOI：
10.1126/science.aad1210
发表时间：
2016-06-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Arbore G;West EE;Spolski R;Robertson AAB;Klos A;Rheinheimer C;Dutow P;Woodruff TM;Yu ZX;O'Neill LA;Coll RC;Sher A;Leonard WJ;Köhl J;Monk P;Cooper MA;Arno M;Afzali B;Lachmann HJ;Cope AP;Mayer-Barber KD;Kemper C
通讯作者：
Kemper C