Fig. 7. High iNOS expression in tumor tissue correlates with favorable survival and T cell signature in colon and kidney cancer patients.

Overall survival analysis of cancer patients with (A) kidney renal clear cell carcinoma (KIRC) or (B) colon adenocarcinoma (COAD) and either high or low mRNA expression for NOS2 (iNOS). Patients from each dataset were split into two groups by median expression level of NOS2. Normalized gene expression (RNAseq) and corresponding clinical data on patients were obtained from The Cancer Genome Atlas (TCGA). Survival curves were compared by log rank (Mantel-Cox) test.

(C) Correlation between expression of NOS2 and CD3E, CD8A, IFNG and PRF1 in Colorectal Adenocarcinoma patients (n=592) from TCGA PanCancer data. Spearman r and P values are shown on the individual plots. Gene expression levels are presented in the log2 form.

(D) Schematic summary of mechanism. We propose that during combined treatment with radiation and exogenous RA, the infiltrating monocytes which are induced by radiation are transformed into iNOS/TNF-α–producing inflammatory macrophages. Through iNOS production the inflammatory macrophages enhance CD4⁺ and CD8⁺ T cell infiltration and the newly arrived T cells produce more IFN-γ to induce even higher levels of Inf-MACs. This positive feedback loop between Inf-MACs and T cells amplifies antitumor innate and adaptive immunity and leads to superior tumor control compared to either treatment alone.