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

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.

TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype.

Pathological angiogenesis associated with wound healing often occurs subsequent to an inflammatory response that includes the secretion of cytokines such as tumor necrosis factor (TNF). Controversy exists on the angiogenic actions of TNF, with it being generally proangiogenic in vivo, but antiangiogenic in vitro. We find that whereas continuous administration of TNF in vitro or in vivo inhibits angiogenic sprouting, a 2- to 3-day pulse stimulates angiogenesis by inducing an endothelial "tip cell" phenotype. TNF induces the known tip cell genes platelet-derived growth factor B (PDGFB) and vascular endothelial cell growth factor receptor-2 (VEGFR2), while at the same time blocking signaling through VEGFR2, thus delaying the VEGF-driven angiogenic response. Notch signaling regulates tip cell function, and we find that TNF also induces the notch ligand jagged-1, through an NFkappaB-dependent mechanism. Enrichment of jagged-1 in tip cells was confirmed by immunofluorescent staining as well as by laser capture microdissection/quantitative reverse-transcription-polymerase chain reaction (qRT-PCR) of tip cells sprouting in vitro. Thus, in angiogenesis, the temporal expression of TNF is critical: it delays angiogenesis initially by blocking signaling through VEGFR2, but in addition by inducing a tip cell phenotype through an NFkappaB-dependent pathway, it concomitantly primes endothelial cells (ECs) for sprouting once the initial inflammatory wave has passed.