Search

Background: Antitumoral immune response has a crucial role in constraining cancer. However, previous studies on cholangiocarcinoma (CCA), a rare and aggressive cancer, have reported contradictory findings on the prognostic impact of tumorinfiltrating T-lymphocytes. We aimed to clarify the effect of tumor-infiltrating CD3+ and CD8+ lymphocytes and PD-1/PD-L1 expression on CCA prognosis. Methods: CD3+, CD8+, and PD-1+ lymphocyte densities, as well as PD-L1 expression rate were analyzed from stained tissue microarray samples from the tumor center and invasive margin of 47 cholangiocarcinomas. The association of CD3+ and CD8+ based Immune cell score (ICS) and its components with overall survival was evaluated, adjusting for age, sex, TNM stage, radicality of surgery, tumor location, and PD-L1 expression on immune cells. Results: Low ICS was a strong independent prognostic factor for worse overall survival (Hazard ratio 9.27, 95% confidence interval 2.72-31.64, P<0.001). Among the ICS components, high CD8+ lymphocyte infiltration at the tumor center had the most evident impact on patient outcome. PD-1 and PD-L1 expression on immune cells did not have a significant impact on overall survival alone; however, PD-L1 positivity seemed to impair survival for ICSlow subgroup. Conclusion: Identifying patient subgroups that could benefit from immunotherapy with PD-1/PD-L1 pathway blockade may help improve treatment strategies for this aggressive cancer. Our findings highlight the importance of evaluating the immune contexture in cholangiocarcinoma, as ICS serves as a strong independent prognostic and selective factor for patients who might benefit from immunotherapy. [ABSTRACT FROM AUTHOR]

Lynch syndrome (LS) is the most common inherited cancer syndrome. It is inherited via a monoallelic germline variant in one of the DNA mismatch repair (MMR) genes. LS carriers have a broad 30% to 80% risk of developing various malignancies, and more precise, individual risk estimations would be of high clinical value, allowing tailored cancer prevention and surveillance. Due to MMR deficiency, LS cancers are characterized by the accumulation of frameshift mutations leading to highly immunogenic frameshift peptides (FSPs). Thus, immune surveillance is proposed to inhibit the outgrowth of MMR‐deficient cell clones. Recent studies have shown that immunoediting during the evolution of MMR‐deficient cancers leads to a counter‐selection of highly immunogenic antigens. The immunogenicity of FSPs is dependent on the antigen presentation. One crucial factor determining antigen presentation is the HLA genotype. Hence, a LS carrier's HLA genotype plays an important role in the presentation of FSP antigens to the immune system, and may influence the likelihood of progression from precancerous lesions to cancer. To address the challenge of clarifying this possibility including diverse populations with different HLA types, we have established the INDICATE initiative (Individual cancer risk by HLA type, http://indicate-lynch.org/), an international network aiming at a systematic evaluation of the HLA genotype as a possible cancer risk modifier in LS. Here we summarize the current knowledge on the role of HLA type in cancer risk and outline future research directions to delineate possible association in the scenario of LS with genetically defined risk population and highly immunogenic tumors. [ABSTRACT FROM AUTHOR]

Circulating microRNAs (c‐miRs) are small noncoding RNA molecules that migrate throughout the body and regulate gene expression. Global c‐miR expression patterns (c‐miRnomes) change with sporadic carcinogenesis and have predictive potential in early detection of cancers. However, there are no studies that have assessed whether c‐miRnomes display similar potential in carriers of inherited pathogenic mismatch‐repair gene variants (path_MMR), known as Lynch syndrome (LS), who are predisposed to highly increased cancer risk. Using high‐throughput sequencing and bioinformatic approaches, we conducted an exploratory analysis to characterize systemic c‐miRnomes of path_MMR carriers, sporadic rectal cancer patients and non‐LS controls. We showed for the first time that cancer‐free path_MMR carriers have a systemic c‐miRnome of 40 differentially expressed c‐miRs that can distinguish them from non‐LS controls. The systemic c‐miRnome of cancer‐free path_MMR carriers also resembles the systemic c‐miRnomes of cancer patients with or without path_MMR. Our pathway analysis linked the found differentially expressed c‐miRs to carcinogenesis. A total of 508 putative target genes were identified for 32 out of 40 differentially expressed c‐miRs, and 238 of them were enriched in cancer‐related pathways. The most enriched c‐miR‐target genes include well‐known oncogenes and tumor suppressor genes such as BCL2, AKT3, PIK3CA, KRAS, NRAS, CDKN1A and PIK3R1. Taken together, our findings suggest that LS and sporadic carcinogenesis share common biological pathways and alterations in these pathways can produce a c‐miR signature which can track potential oncogenic stress in cancer‐free path_MMR carriers. Therefore, c‐miRs hold potential in monitoring the LS risk stratification patterns during clinical surveillance or cancer management. [ABSTRACT FROM AUTHOR]

Simple Summary: The lung is the second most common site of metastases in colorectal cancer (CRC). The aim of our study was to evaluate the prognostic value of CD3+ and CD8+ T-cell density based immune cell score (ICS) and PD-1/PD-L1 expression in resected pulmonary metastases of microsatellite stable CRC. The T-cell infiltration was higher in the first pulmonary metastases compared to primary tumour. Pulmonary metastases with high ICS had improved survival compared to low ICS after adjusting for confounders. High tumour cell PD-L1 expression was associated with favourable prognosis. Our results might have clinical feasibility in planning future therapies. The objective of this study was to evaluate the prognostic value of CD3+ and CD8+ based immune cell score (ICS), programmed death -1 (PD-1) and programmed death ligand -1 (PD-L1) in pulmonary metastases of proficient mismatch repair colorectal cancer (CRC) patients. A total of 101 pulmonary metastases and 62 primary CRC tumours were stained for CD3+, CD8+, PD-1 and PD-L1 expression. The prognostic value of ICS, PD-1/PD-L1 expression in 67 first pulmonary metastases and 61 primary CRC tumour was analysed. Comparative analysis was also performed between primary tumours and pulmonary metastases, as well as between T-cell densities and PD-1/PD-L1 expression. The 5-year overall survival rates of low, intermediate, and high ICS in pulmonary metastases were 10.0%, 25.5% and 47.0% (p = 0.046), respectively. Patients with high vs. low ICS in pulmonary metastases had a significantly better 5-year survival (adjusted HR 0.25, 95% CI 0.09–0.75, p = 0.013). High tumour cell PD-L1 expression in the pulmonary metastases was associated with improved survival (p = 0.024). Primary tumour CD8+ expression was significantly correlated with all T-cell densities in pulmonary metastases. Conclusion: The ICS evaluated from the resected pulmonary metastases of CRC showed significant prognostic value. High PD-L1 expression in pulmonary metastases is associated with favourable prognosis. [ABSTRACT FROM AUTHOR]

Tumor necrosis has been reported to represent an independent prognostic factor in colorectal cancer, but its evaluation methods have not been described in sufficient detail to introduce tumor necrosis evaluation into clinical use. To study the potential of tumor necrosis as a prognostic indicator in colorectal cancer, criteria for 3 methods for its evaluation were defined: the average percentage method (tumor necrosis percentage of the whole tumor), the hotspot method (tumor necrosis percentage in a single hotspot), and the linear method (the diameter of the single largest necrotic focus). Cox regression models were used to calculate cancer-specific mortality hazard ratios (HRs) for tumor necrosis categories in 2 colorectal cancer cohorts with more than 1800 cases. For reproducibility assessment, 30 cases were evaluated by 9 investigators, and Spearman's rank correlation coefficients and Cohen's kappa coefficients were calculated. We found that all 3 methods predicted colorectal cancer-specific survival independent of other prognostic parameters, including disease stage, lymphovascular invasion, and tumor budding. The greatest multivariable HRs were observed for the average percentage method (cohort 1: HR for ≥ 40% vs. <3% 3.03, 95% CI, 1.93-4.78; cohort 2: HR for ≥ 40% vs. < 3% 2.97; 95% CI, 1.63-5.40). All 3 methods had high reproducibility, with the linear method showing the highest mean Spearman's correlation coefficient (0.91) and Cohen's kappa (0.70). In conclusion, detailed criteria for tumor necrosis evaluation were established. All 3 methods showed good reproducibility and predictive ability. The findings pave the way for the use of tumor necrosis as a prognostic factor in colorectal cancer., Competing Interests: Conflicts of Interest and Source of Funding: This study was funded by Cancer Foundation Finland (59-5619 to J.P.V.), Finnish Medical Foundation (6021 to J.P.V.; 6259 to M.K.), Oulu Medical Research Foundation (to M.K.), Sigrid Jusélius Foundation (230229 to J.P.V.), and Finnish State Research Funding (to M.J.M. and J.P.V.). T.T. Seppälä reports consultation fees from Amgen Finland, Tillots Pharma, and Nouscom, being a co-owner and CEO of Healthfund Finland Ltd, and a position in the Clinical Advisory Board and a minor shareholder of LS Cancer Diag Ltd. For the remaining authors, none were declared., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Purpose: Immunoscore® is a prognostic parameter based on densities of lymphocyte populations in the tumor center and invasive margin. Immunoscore® is validated in colorectal cancer as a high Immunoscore® is associated with longer survival. Previous studies have suggested that Immunoscore® may also predict oncological outcomes in clear-cell renal cell carcinoma (ccRCC). This study aims to assess the prognostic role of immune cell score in ccRCC., Material and Methods: All patients with ccRCC undergoing surgery between 2007 and 2020 in Central Finland Central Hospital were retrospectively identified. CD3+ and CD8+ cell densities were calculated from tissue samples to determine the immune cell score using Immunoscore® principles. Receiver-operating characteristic analysis, Kaplan-Meier survival curve, and Cox regression were used to evaluate the association between immune cell score and survival., Results: A total of 203 patients (mean age 66.5 years) were identified. The median follow-up time was 6.2 years. Based on the immune cell score, the patients were divided into three groups: low, intermediate, and high. In Cox regression analysis, adjusted with age, sex, and Charlson Comorbidity Index, no significant differences in disease-specific mortality were observed among the three groups. The hazard ratios (HRs) for disease-specific mortality were 0.93 (95% confidence interval [CI] 0.48-1.79) and 1.12 (0.52-2.37) for intermediate- and high-immune cell score groups when compared to low-immune cell score group, respectively., Interpretation: This study found no association between immune cell score and survival. These results indicate that immune cell score may not serve as a prognostic tool in ccRCC.