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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.sup.+] and [CD8.sup.+] 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., Introduction Higher vertebrates have developed innate protective mechanisms that can detect stress-induced cues triggered by infection, injury, or carcinogenesis. One example of cytosolic sensors of cellular perturbations are the nucleotide-binding [...]

MRP-1 is implicated in multidrug resistance and was described as prognostic in high-risk patients with soft-tissue sarcoma (STS) in a previous study. The current research aimed to validate MRP-1 prognostic/predictive value in localized sarcomas treated with anthracyclines plus ifosfamide within the ISG-1001 phase III study. In addition, the inhibitory activity on MRP-1 was investigated in preclinical studies to identify new combinations able to increase the efficacy of standard chemotherapy in STS. MRP-1 expression was assessed by IHC in tissue microarrays from patients with STS and tested for correlation with disease-free survival (DFS) and overall survival (OS). In vitro studies tested the efficacy of MRP-1 inhibitors (nilotinib, ripretinib, selumetinib, and avapritinib) in sarcoma cell lines. The effect of combinations of the most active MRP-1 inhibitors and chemotherapy was measured on the basis of apoptosis. MRP-1 was evaluable in 231 of 264 cases who entered the study. MRP-1 expression (strong intensity) was independently associated with worse DFS [HR, 1.78; 95% confidence interval (CI), 1.11-2.83; P = 0.016], in the multivariate analysis, with a trend for a worse OS (HR, 1.78; 95% CI, 0.97-3.25; P = 0.062). In vitro studies showed that the addition of MRP-1 inhibitors (nilotinib or avapritinib) to doxorubicin plus palifosfamide, significantly increased cell death in SK-UT-1 and CP0024 cell lines. MRP-1 is an adverse predictive factor in localized high-risk patients with STS treated with neoadjuvant anthracyclines plus ifosfamide followed by surgery. In vitro findings support the clinical assessment of the combination of chemotherapy and MRP-1 inhibitors as a promising strategy to overcome the drug ceiling effect for chemotherapy., (©2021 American Association for Cancer Research.)

Background: Pure or metaplastic squamous cell carcinoma (SCC) of the breast is a rare entity with an unclear pathogeny and aggressive clinical behaviour. An attempt was made to characterize its differential immunohistochemical and biological profile., Patients and Methods: Twenty-seven cases of SCC (pure or not) of the breast were matched with 27 ductal invasive carcinomas (IDC) for age, tumour size, nodal involvement and year of diagnosis. The expression levels of oestrogen receptor (ER), progesterone receptor (PR), Ki-67, epidermal growth factor receptor (EGFR), HER2, Cyclin Bl, hTERT, cytokeratins (CK) 5/6 and p63 were determined immunohistochemically in both cohorts. The presence of the human papilloma virus (HPV) genome was investigated by polymerase chain reaction (PCR)., Results: Pure and metaplastic SCC displayed common profiles typifying a basal origin: they never expressed ER or PR, were HER2-negative in 93% of cases, exhibited positivity for CK5/6 or EGF-R in 75% and 85%, and for p63 in 70% of cases and were highly proliferative. These profiles were markedly different from those of matched controls (p<0.001 for five markers) except for HER2 and hTERT. The HPVgenome was detected in 2 out of 14 cases (14%) of SCC., Conclusion: The expression profile of SCC of the breast was markedly different from that of IDC. A typical "basal-like" phenotype was displayed that may explain part of their behaviour and justify specific therapeutic approaches. HPV infection was not a leading oncogenic event in SCC of the breast.