Human NLRC4 expression promotes cancer survival and associates with type I interferon signaling and immune infiltration
Charlotte Domblides, Steven Crampton, Hong Liu, Juliet M. Bartleson, Annie Nguyen, Claudia Champagne, Emily E. Landy, Lindsey Spiker, Christopher Proffitt, Sunil Bhattarai, Anissa P. Grawe, Matias Fuentealba Valenzuela, Lydia Lartigue, Isabelle Mahouche, Jeremy Dupaul-Chicoine, Kazuho Nishimura, Félix Lefort, Marie Decraecker, Valérie Velasco, Sonia Netzer, Vincent Pitard, Christian Roy, Isabelle Soubeyran, Victor Racine, Patrick Blanco, Julie Déchanet-Merville, Maya Saleh, Scott W. Canna, David Furman, Benjamin Faustin
Charlotte Domblides, Steven Crampton, Hong Liu, Juliet M. Bartleson, Annie Nguyen, Claudia Champagne, Emily E. Landy, Lindsey Spiker, Christopher Proffitt, Sunil Bhattarai, Anissa P. Grawe, Matias Fuentealba Valenzuela, Lydia Lartigue, Isabelle Mahouche, Jeremy Dupaul-Chicoine, Kazuho Nishimura, Félix Lefort, Marie Decraecker, Valérie Velasco, Sonia Netzer, Vincent Pitard, Christian Roy, Isabelle Soubeyran, Victor Racine, Patrick Blanco, Julie Déchanet-Merville, Maya Saleh, Scott W. Canna, David Furman, Benjamin Faustin
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Research Article Immunology Oncology

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

Abstract

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.

Authors

Charlotte Domblides, Steven Crampton, Hong Liu, Juliet M. Bartleson, Annie Nguyen, Claudia Champagne, Emily E. Landy, Lindsey Spiker, Christopher Proffitt, Sunil Bhattarai, Anissa P. Grawe, Matias Fuentealba Valenzuela, Lydia Lartigue, Isabelle Mahouche, Jeremy Dupaul-Chicoine, Kazuho Nishimura, Félix Lefort, Marie Decraecker, Valérie Velasco, Sonia Netzer, Vincent Pitard, Christian Roy, Isabelle Soubeyran, Victor Racine, Patrick Blanco, Julie Déchanet-Merville, Maya Saleh, Scott W. Canna, David Furman, Benjamin Faustin

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Figure 5

NLRC4 expression is associated with DC2 and DC3 cells and CD4+ and CD8+ T cell tumor infiltrates in cancer patients.

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NLRC4 expression is associated with DC2 and DC3 cells and CD4+ and CD8+...
(A) Left: Expression correlation between NLRC4, NLRP10, or TMEM173 (STING) and various tumor-infiltrating DC subsets in CRC (COAD, READ), lung cancer (LUSC, LUAD), or melanoma (SKCM). The various DC subset gene signatures used (for DC1–DC6) were obtained from scRNA-seq of human blood. Right: Scatter plots showing correlation of gene expression between NLRC4, or NLRP10, or TMEM173, and DC2 or DC3 gene signatures in COAD patient tumors. COAD data sets used were obtained from TCGA cohort. (B) Left: Gene expression correlation between NLRC4, NLRP10, or TMEM173 (STING) and CD4 or CD8A in patient tumors; correlation coefficient R is represented by the size of dot, and log10(P value) is represented by the color of the dot. Right: Scatter plots showing correlation of gene expression between NLRC4, or NLRP10, or TMEM173 and CD4 or CD8A in COAD patient tumors. Correlation coefficient R and P values are indicated. (C) Gene expression correlation between NLRC4, CASP1, IL1B, or IL18 and CD4 or CD8A in patient tumors. For A–C, data analysis was performed using TCGA patient database cohort; correlation coefficient R is represented by the size of the dots, and log10(P value) is represented by the color of the dot. COAD, colon adenocarcinoma; READ, rectum adenocarcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; SKCM, skin cutaneous melanoma.