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Muscarinic acetylcholine receptor M3 (M3R) has repeatedly been shown to be prominently expressed in human colorectal cancer (CRC), playing roles in proliferation and cell invasion. Its therapeutic targetability has been suggested in vitro and in animal models. We aimed to investigate the clinical role of MR3 expression in CRC for human survival. Surgical tissue samples from 754 CRC patients were analyzed for high or low immunohistochemical M3R expression on a clinically annotated tissue microarray (TMA). Immunohistochemical analysis was performed for established immune cell markers (CD8, TIA-1, FOXP3, IL 17, CD16 and OX 40). We used Kaplan-Meier curves to evaluate patients' survival and multivariate Cox regression analysis to evaluate prognostic significance. High M3R expression was associated with increased survival in multivariate (hazard ratio (HR) = 0.52; 95% CI = 0.35-0.78; p = 0.001) analysis, as was TIA-1 expression (HR = 0.99; 95% CI = 0.94-0.99; p = 0.014). Tumors with high M3R expression were significantly more likely to be grade 2 compared to tumors with low M3R expression (85.7% vs. 67.1%, p = 0.002). The 5-year survival analysis showed a trend of a higher survival rate in patients with high M3R expression (46%) than patients with low M3R expression CRC (42%) ( p = 0.073). In contrast to previous in vitro and animal model findings, this study demonstrates an increased survival for CRC patients with high M3R expression. This evidence is highly relevant for translation of basic research findings into clinically efficient treatments.

Background: Despite improvements in therapy of colorectal cancer, some patients will present occurrence of recurrence either locally or distantly. Tumor metastasis constitutes the major cause of cancer-associated morbidity and mortality. Nectin-1 belongs to the family of immunoglobulin-like cell adhesion molecules that contribute to the formation of cell-cell adhesions and regulate a series of cellular activities including cell polarization, differentiation, movement, proliferation, and survival. Expression of Nectin-1 in malignant tumors has been associated with aggressive tumor phenotypes., Objectives: The aim of the present study was to assess Nectin-1 expression patterns in colorectal cancer and to investigate its clinical significance., Methods: Nectin-1 expression was assessed via immunohistochemistry in surgical specimens of a cohort comprised of 111 patients with primary resectable colorectal cancer. Results were correlated with clinicopathological characteristics and survival data. Progression-free survival was defined as the primary outcome of the present study., Results: Nectin-1 was strongly expressed in the cytoplasm of colorectal cancer cells. High Nectin-1 expression was associated with advanced stage of disease (p = 0.012) and lymph node metastasis (p = 0.007). Progression-free survival of patients exhibiting high expression of Nectin-1 in the first 36 months after surgery was significantly worse compared to patients with low expression of Nectin-1 (55.7%, 95% CI = 47-70, vs. 82.1%, 95% CI = 69-93, p = 0.014) and independent of other clinicopathological characteristics (HR = 0.389, 95% CI = 0.156-0.972, p = 0.043)., Conclusion: Nectin-1 expression in colorectal cancer is associated with a significantly worse 3-year progression-free survival identifying therefore a group of patients with high risk for early disease recurrence., (© 2019 S. Karger AG, Basel.)

Purpose: Tumor infiltration by different T lymphocyte subsets is known to be associated with favorable prognosis in colorectal cancer. Still debated is the role of innate immune system. We investigated clinical relevance, phenotypes, and functional features of colorectal cancer-infiltrating CD66b + neutrophils and their crosstalk with CD8 + T cells. Experimental Design: CD66b + and CD8 + cell infiltration was analyzed by IHC on a tissue microarray including >650 evaluable colorectal cancer samples. Phenotypic profiles of tissue-infiltrating and peripheral blood CD66b + cells were evaluated by flow cytometry. CD66b + /CD8 + cells crosstalk was investigated by in vitro experiments. Results: CD66b + cell infiltration in colorectal cancer is significantly associated with increased survival. Interestingly, neutrophils frequently colocalize with CD8 + T cells in colorectal cancer. Functional studies indicate that although neutrophils are devoid of direct antitumor potential, coculture with peripheral blood or tumor-associated neutrophils (TAN) enhances CD8 + T-cell activation, proliferation, and cytokine release induced by suboptimal concentrations of anti-CD3 mAb. Moreover, under optimal activation conditions, CD8 + cell stimulation in the presence of CD66b + cells results in increasing numbers of cells expressing CD45RO/CD62L "central memory" phenotype. Importantly, combined tumor infiltration by CD66b + and CD8 + T lymphocytes is associated with significantly better prognosis, as compared with CD8 + T-cell infiltration alone. Conclusions: Neutrophils enhance the responsiveness of CD8 + T cells to T-cell receptor triggering. Accordingly, infiltration by neutrophils enhances the prognostic significance of colorectal cancer infiltration by CD8 + T cells, suggesting that they might effectively promote antitumor immunity. Clin Cancer Res; 23(14); 3847-58. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: It remains a matter of debate whether colorectal cancer resection in an emergency setting negatively impacts on survival. Our objective was therefore to assess the impact of urgent versus elective operation on overall and disease-free survival in patients undergoing resection for colorectal cancer by using propensity score adjusted analysis., Methods: In a single-center study patients operated for colorectal cancer between 1989 and 2013 were identified from a prospectively maintained database. Median follow-up was 44 months. Patients with neoadjuvant treatment were excluded. The impact of urgent operation on overall and disease-free survival was assessed using both Cox regression and propensity score analyses., Results: Of 747 patients with colorectal cancer, 84 (11%) had urgent and 663 elective cancer resection. The propensity score revealed strongly biased patient characteristics (0.22 ± 0.16 vs. 0.10 ± 0.09; P < 0.001). In unadjusted analysis urgent operation was associated with a 35% increased risk of overall mortality (hazard ratio(HR) of death = 1.35, 95% confidence interval(CI):1.02-1.78, P = 0.045). In risk-adjusted Cox regression analysis urgent operation was not associated with poor overall (HR = 1.08, 95%CI:0.79-1.48; P = 0.629) or disease-free survival (HR = 1.02, 95%CI:0.76-1.38; P = 0.877). Similarly in propensity score analysis urgent operation did not influence overall (HR = 0.98, 95% CI:0.74-1.29), P = 0.872) and disease-free survival (HR = 0.89, 95%CI:0.68 to 1.16, P = 0.387)., Conclusions: This study provides evidence that worse oncologic outcomes after urgent operation for colorectal cancer are caused by clinical circumstances and not due to the urgent operation itself. Urgent operation is not a risk factor for colorectal cancer resection.

The goal of this study was to determine the frequency of HLA class II antigen expression in colorectal carcinoma (CRC) tumors, its association with the clinical course of the disease, and the underlying mechanism(s). Two tissue microarrays constructed with 220 and 778 CRC tumors were stained with HLA-DR, DQ, and DP antigen-specific monoclonal antibody LGII-612.14, using the immunoperoxidase staining technique. The immunohistochemical staining results were correlated with the clinical course of the disease. The functional role of HLA class II antigens expressed on CRC cells was analyzed by investigating their in vitro interactions with immune cells. HLA class II antigens were expressed in about 25% of the 220 and 21% of the 778 tumors analyzed with an overall frequency of 23%. HLA class II antigens were detected in 19% of colorectal adenomas. Importantly, the percentage of stained cells and the staining intensity were significantly lower than those detected in CRC tumors. However, HLA class II antigen staining was weakly detected only in 5.4% of 37 normal mucosa tissues. HLA class II antigen expression was associated with a favorable clinical course of the disease. In vitro stimulation with interferon gamma (IFNγ) induced HLA class II antigen expression on two of the four CRC cell lines tested. HLA class II antigen expression on CRC cells triggered interleukin-1β (IL-1β) production by resting monocytes. HLA class II antigen expression in CRC tumors is a favorable prognostic marker. This association may reflect stimulation of IL-1β production by monocytes.

The prognostic significance of macrophage and natural killer (NK) cell infiltration in colorectal carcinoma (CRC) microenvironment is unclear. We investigated the CRC innate inflammatory infiltrate in over 1,600 CRC using two independent tissue microarrays and immunohistochemistry. Survival time was assessed using the Kaplan-Meier method and Cox proportional hazards regression analysis in a multivariable setting. Spearman's rank correlation tested the association between macrophage and lymphocyte infiltration. The Basel study included over 1,400 CRCs. The level of CD16+ cell infiltration correlated with that of CD3+ and CD8+ lymphocytes but not with NK cell infiltration. Patients with high CD16+ cell infiltration (score 2) survived longer than patients with low (score 1) infiltration (p = 0.008), while no survival difference between patients with score 1 or 2 for CD56+ (p = 0.264) or CD57+ cell (p = 0.583) infiltration was detected. CD16+ infiltrate was associated with improved survival even after adjusting for known prognostic factors including pT, pN, grade, vascular invasion, tumor growth and age [(p = 0.001: HR (95% CI) = 0.71 (0.6-0.9)]. These effects were independent from CD8+ lymphocyte infiltration [(p = 0.036: HR (95% CI) = 0.81 (0.7-0.9)] and presence of metastases [(p = 0.002: HR (95% CI) = 0.43 (0.3-0.7)]. Phenotypic studies identified CD16+ as CD45+CD33+CD11b+CD11c+ but CD64- HLA-DR-myeloid cells. Beneficial effects of CD16+ cell infiltration were independently validated by a study carried out at the University of Athens confirming that patients with CD16 score 2 survived longer than patients with score 1 CRCs (p = 0.011). Thus, CD16+ cell infiltration represents a novel favorable prognostic factor in CRC., (Copyright © 2010 UICC.)