Human NLRC4 expression promotes cancer survival and associates with type I interferon signaling and immune infiltration

被引：6

作者：

Domblides, Charlotte ^{[1
,2
,3
]}

Crampton, Steven ^{[4
]}

Liu, Hong ^{[5
,6
]}

Bartleson, Juliet M. ^{[7
]}

Nguyen, Annie ^{[4
]}

Champagne, Claudia ^{[8
]}

Landy, Emily E. ^{[9
]}

Spiker, Lindsey ^{[8
]}

Proffitt, Christopher ^{[5
,6
]}

Bhattarai, Sunil ^{[4
]}

Grawe, Anissa P. ^{[7
]}

Valenzuela, Matias Fuentealba ^{[7
]}

Lartigue, Lydia ^{[10
]}

Mahouche, Isabelle ^{[10
]}

Dupaul-Chicoine, Jeremy ^{[6
]}

Nishimura, Kazuho ^{[5
,6
]}

Lefort, Felix ^{[2
,3
]}

Decraecker, Marie ^{[2
]}

Velasco, Valerie ^{[11
]}

Netzer, Sonia ^{[1
,2
]}

Pitard, Vincent ^{[1
,2
]}

Roy, Christian ^{[5
,6
]}

Soubeyran, Isabelle ^{[11
]}

Racine, Victor ^{[12
,13
]}

Blanco, Patrick ^{[1
]}

Dechanet-Merville, Julie ^{[1
,2
]}

Saleh, Maya ^{[14
]}

Canna, Scott W. ^{[15
,16
]}

Furman, David ^{[7
,17
]}

Faustin, Benjamin ^{[1
,4
]}

机构：

[1] Univ Bordeaux, Bordeaux, France

[2] Bordeaux Univ, ImmunoConcEpt, CNRS UMR 5164, INSERM ERL 1303, Bordeaux, France

[3] Univ Hosp Bordeaux, Dept Med Oncol, Bordeaux, France

[4] Johnson & Johnson Innovat Med, Discovery Immunol, San Diego, CA USA

[5] Takeda Pharmaceut, GI & Immune Oncol DDUs, San Diego, CA USA

[6] Takeda Pharmaceut, GI & Immune Oncol DDUs, Cambridge, MA USA

[7] Buck Inst Res Aging, 8001 Redwood Blvd, Novato, CA 94945 USA

[8] McGill Univ, Dept Med, Montreal, PQ, Canada

[9] Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA USA

[10] Univ Pittsburgh, Sch Publ Hlth, Dept Genet, Pittsburgh, PA USA

[11] INSERM, ACT U1218, F-33000 Bordeaux, France

[12] Inst Bergonie, Comprehens Canc Ctr, Dept Biopathol, Bordeaux, France

[13] Hop St Eloi, QuantaCell, IRMB, Montpellier, France

[14] INRS Sante Biotechnol, Laval, PQ, Canada

[15] Childrens Hosp Philadelphia, Pediat Rheumatol, Philadelphia, PA USA

[16] Univ Penn, Perelman Sch Med, Philadelphia, PA USA

[17] Stanford Sch Med, Stanford Immunomes Project 1000, Stanford, CA USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2024年 / 134卷 / 11期

关键词：

COMPREHENSIVE ANALYSIS; DENDRITIC CELLS; AUTOINFLAMMATION; ENTEROCOLITIS; ACTIVATION; CASPASE-1; MUTATION;

D O I：

10.1172/JCI166085

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

The immune system can control cancer progression. However, even though some innate immune sensors of cellular stress are expressed intrinsically in epithelial cells, their potential role in cancer aggressiveness and subsequent overall survival in humans is mainly unknown. Here, we show that nucleotide -binding oligomerization domain-like receptor (NLR) family CARD domain-containing 4 (NLRC4) is downregulated in epithelial tumor cells of patients with colorectal cancer (CRC) by using spatial tissue imaging. Strikingly, only the loss of tumor NLRC4, but not stromal NLRC4, was associated with poor immune infiltration (mainly DCs and CD4 + and CD8 + T cells) and accurately predicted progression to metastatic stage IV and decrease in overall survival. By combining multiomics approaches, we show that restoring NLRC4 expression in human CRC cells triggered a broad inflammasome-independent immune reprogramming consisting of type I interferon (IFN) signaling genes and the release of chemokines and myeloid growth factors involved in the tumor infiltration and activation of DCs and T cells. Consistently, such reprogramming in cancer cells was sufficient to directly induce maturation of human DCs toward a Th1 antitumor immune response through IL -12 production in vitro. In multiple human carcinomas (colorectal, lung, and skin), we confirmed that NLRC4 expression in patient tumors was strongly associated with type I IFN genes, immune infiltrates, and high microsatellite instability. Thus, we shed light on the epithelial innate immune sensor NLRC4 as a therapeutic target to promote an efficient antitumor immune response against the aggressiveness of various carcinomas.

引用

页数：19