Human NLRC4 expression promotes cancer survival and associates with type I interferon signaling and immune infiltration
Charlotte Domblides, … , David Furman, Benjamin Faustin
Charlotte Domblides, … , David Furman, Benjamin Faustin
Published April 23, 2024
Citation Information: J Clin Invest. 2024;134(11):e166085. https://doi.org/10.1172/JCI166085.
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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 1

Loss of tumor epithelial NLRC4 is associated with aggressive metastatic stage IV, and decreased overall survival of CRC patients.

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Loss of tumor epithelial NLRC4 is associated with aggressive metastatic ...
(A) Left: Association between protein expression levels of tumor epithelial NLRC4, IL-18, or IL-1β and patient overall survival in the Bergonié Cancer Institute cohort. When available, patients were stratified based on protein expression levels of NLRC4, IL-1β, or IL-18, as high versus low expression in the colon epithelium (inside the cytokeratin mask) or in the stroma (outside the cytokeratin mask). NC, could not be calculated. A log-rank test stratified according to protein expression was used. Asterisks indicate P values between high versus low expression of markers either inside or outside the mask. Right: Protein expression of tumor epithelial NLRC4, IL-18, or IL-1β, in various CRC tumor stages, classified as stage I–II (localized), III (locally advanced), or IV (metastatic disease) (from the Bergonié cohort). COAD, colon adenocarcinoma; READ, rectum adenocarcinoma; CHOL, cholangiocarcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by 1-way ANOVA (parametric) or Kruskal-Wallis (nonparametric) test. (B) Top left: Representative image of polyps of a 6-month-old ApcMin/+ mouse in the small intestine (SI) according to their position (P, proximal; M, middle; or D, distal) and in the colon. Top right: H&E staining of healthy SI and polyp-containing section of a 6-month-old ApcMin/+ mouse. Original magnification, ×4. Bottom: Quantification of the number of polyps in the SI (n = 17) and the colon of ApcMin/+ mice (n = 17), and the size distribution of polyps from 6-month-old ApcMin/+ mice in the SI and colon. (C) Representative immunofluorescence images of SI tissue sections at 3 or 6 months of ApcMin/+ mice stained with anti-NLRC4 antibody (red). Anti-cytokeratin (green) and Hoechst (blue) were used to stain epithelial cells and nuclear morphology, respectively. Boxes indicate regions (150 × 150 μm) used to quantify NLRC4 staining in tumor (T) portion of the tissue. Graph shows NLRC4 expression level (MFI) in tumor region of SI at 3 or 6 months in ApcMin/+ mice. Data are mean ± SEM of 21–27 distinct normal/tumor regions, 3 regions per mouse, 7–9 mice per time point. ****P < 0.0001 by 2-tailed Student’s t test.