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Expression of the High Affinity Neurotensin Receptor (NTSR1) Defines an Immune-Cold, Poor-Prognosis Colorectal Cancer (CRC) Subtype
*Haoming Wu, *Yang Wang, *Dana Napier, *Chi Wang, *Heidi Weiss, *Jing Li, B. Mark Evers
Markey Cancer Center, Lexington, Kentucky

OBJECTIVE: In a manner analogous to hormone-sensitive breast and prostate cancers, certain CRCs are also hormonally responsive. We have shown that the proliferation of CRCs expressing NTSR1 is stimulated with the addition of NTS and inhibited with NTSR1 blockade. Moreover, we were the first to report NTSR1 expression in T cells and to propose that NTSR1 may exert suppressive effects on immune cells. However, whether NTSR1 activation restricts CRC immune cell infiltration and shapes an immune-cold tumor microenvironment as well as the underlying molecular mechanisms and prognostic considerations remain largely unexplored. METHODS: (1) NTSR1 expression and overall survival (OS) were analyzed in 190 CRC patients from a single-institutional cohort. Immune contexture was characterized by differential gene expression, KEGG pathway enrichment, and immune deconvolution (CIBERSORT). (2) For external validation, the TCGA database was queried using gene expression profiling analysis (GEPIA) to assess OS, and gene correlation analyses and TIMER2.0 were used to assess correlations between NTSR1 and tumor-infiltrating immune cell subsets. (3) The functional effect of NTSR1 signaling on T cell infiltration was tested in 3D CRC T cell spheroid co-cultures treated with NTS or the NTSR1 antagonist SR48692. RESULTS: (1) In the institutional cohort, high NTSR1 expression was associated with shorter OS (P = 0.039), reduced infiltration of activated CD4+ T-cells, and increased expression of immunosuppressive genes (Fig. 1). Transcriptomic profiling identified a distinct NTSR1-high signature marked by epithelial barrier reinforcement and G-protein coupled receptor (GPCR) signaling activation. Mucin and keratin genes were upregulated, suggesting a denser mucosal/structural barrier that may impede T cell trafficking. Neuroactive GPCRs and chemosensory receptors were enriched, consistent with prominent olfactory transduction pathway activation. Higher expression of immune-modulatory and adhesion/ECM genes indicated an immunosuppressive, stromally remodeled microenvironment unfavorable to lymphocyte entry. (2) Using TCGA data, patients with high NTSR1 likewise had worse OS (P = 0.045). NTSR1 expression displayed significant positive correlations with multiple immune inhibitory genes, such as CD274 and IL10. TIMER2.0 analysis further revealed significant negative correlations between NTSR1 and CD4+ T cell subsets (Fig. 2). (3) NTS-driven NTSR1 activation limited T cell infiltration into tumor spheroids, whereas SR48692 restored T cell entry, demonstrating a direct immune-exclusion effect. CONCLUSIONS: High NTSR1 expression identifies an immune-cold, poor-prognosis CRC subtype. By restricting T cell infiltration and activation, NTSR1 acts as a driver of immune evasion. Pharmacologic inhibition reverses this phenotype, supporting NTSR1 as a prognostic biomarker and a promising therapeutic target for combination immunotherapies, including CAR-T based strategies.


Figure 1. NTSR1-high colorectal cancers exhibit worse survival and an immune-cold signature in the institutional cohort (n=190).