No abstract

The combined analysis of CD8(+) plus CD45RO(+) cells in specific tumor regions could provide a useful criterion for the prediction of tumor recurrence and survival in patients with early-stage colorectal cancer.

Purpose: To determine whether the tumor immune infiltrate, as recently evaluated with the Immunoscore methodology, could be a useful prognostic marker in patients with rectal cancers.Experimental design: The influence of the immune infiltrate on patient's outcome was investigated in patients with or without preoperative chemoradiation therapy (pCRT). The density of total (CD3 þ ) and cytotoxic (CD8 þ ) T lymphocytes was evaluated by immunohistochemistry and quantified by a dedicated image analysis software in surgical specimens of patients with rectal cancer (n ¼ 111) who did not receive pCRT and in tumor biopsies performed before pCRT from additional 55 patients. The results were correlated with tumor recurrence, patient's survival, and response to pCRT.Results: The densities of CD3 þ and CD8 þ lymphocytes and the associated Immunoscore (from I0 to I4)were significantly correlated with differences in disease-free and overall survival (HR, 1.81 and 1.72, respectively; all P < 0.005). Cox multivariate analysis supports the advantage of the Immunoscore compared with the tumor-node-metastasis (TNM) staging in predicting recurrence and survival (all P < 0.001). Lymph node ratio added information in a prognostic model (all P < 0.05). In addition, high infiltration of CD3 þ and CD8 þ lymphocytes in tumor biopsies was associated with downstaging of the tumor after pCRT (CD3 þ cells; Fisher exact test P ¼ 0.01). Conclusions:The Immunoscore could be a useful prognostic marker in patients with rectal cancer treated by primary surgery. The determination of the immune infiltrate in biopsies before treatment could be a valuable information for the prediction of response to pCRT.

Response to treatment and prolonged survival of metastatic CRC patients were statistically significantly associated with high-immune densities quantified into the least immune-infiltrated metastasis.

Highlights d Inter-and intra-metastatic immune infiltrates are heterogeneous in colorectal cancer d T cell densities from metastases increase following anti-EGFR treatment d Immunoscore (IS) outperforms PDL1 staining in metastatic biopsy diagnostic accuracy d IS and TB score from the least-infiltrated metastasis are most survival associated

The prognosis of colon cancer (CC) is dictated by tumor infiltrating lymphocytes, including T follicular helper cells (TFH), and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of TFH-driven responses.Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IEC) and the accumulation of TFH cells in CC in patients and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IEC elicited PD1 + TFH in an IL-1R1 and IL-12 dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD1 blockade in CC, independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC. NMED-A98927: Roberti MP et al. In revision for Nature Medicine

The high frequency of CFHR1 deletion in aHUS patients is restricted to the subgroups of patients presenting with anti-FH autoantibodies or, to a lesser degree, CFI mutation. These results suggest that the CFHR1 deletion plays a secondary role in susceptibility to aHUS.

Background: The Immunoscore (IS), which prognostically classifies stage IeIII colon cancer (CC) patients, was evaluated in the International Duration Evaluation of Adjuvant Therapy (IDEA) France cohort study investigating 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy in stage III CC patients. Patients and methods: Densities of CD3þ and CD8þ T cells in the tumor and invasive margin were determined by immunohistochemistry, quantified by digital pathology, and converted to IS. Mismatch repair status was determined by immunohistochemistry or by pentaplex PCR. Prediction of disease-free survival (DFS) by IS was analyzed by a multivariable Cox regression model in each study arm. Harrell's C-statistics were used to investigate the IS performance. Results: Samples of 1322 patients were available. IS Low, Intermediate (Int), and High were observed in 43.6%, 47.0%, and 9.4% of patients, respectively. IS Low identified patients at higher risk of relapse or death compared with Int þ High [hazard ratio (HR) ¼ 1.54; 95% confidence interval (CI) 1.24e1.93, P ¼ 0.0001]. The 3-year DFS was 66.80% (95% CI 62.23e70.94) for IS Low and 77.14% (95% CI 73.50e80.35) for IS Int þ High. In multivariable analysis, IS remained significantly independently associated with DFS (P ¼ 0.003) when adjusted for sex, histological grade, T/N stage, and microsatellite instability. For mFOLFOX6-treated patients (91.6% of the cohort), a statistical significant interaction was observed for the predictive value of IS for treatment duration (3 versus 6 months) in terms of DFS (P ¼ 0.057). IS Int þ High significantly predicted benefit of 6 months of treatment (HR ¼ 0.53; 95% CI 0.37e0.75; P ¼ 0.0004), including clinically low-and high-risk stage III CC (all P < 0.001). Conversely, patients with IS Low (46.4%) did not significantly benefit from the 6-month mFOLFOX6 versus the 3-month mFOLFOX6. Conclusions: The prognostic value of IS for DFS was confirmed in patients with stage III CC treated with oxaliplatinbased chemotherapy. Its predictive value for DFS benefit of longer duration of mFOLFOX6 adjuvant treatment was found in IS Int þ High. These results will be validated in an external independent cohort.