Abstract
OX40 is a TNF receptor family member expressed by activated T cells. Its triggering by OX40 ligand promotes lymphocyte survival and memory generation. Anti-OX40 agonistic monoclonal antibodies (mAb) are currently being tested in cancer immunotherapy. We explored the prognostic significance of tumor infiltration by OX40+ cells in a large colorectal cancer (CRC) collective. OX40 gene expression was analyzed in 50 freshly excised CRC and corresponding healthy mucosa by qRT-PCR. A tissue microarray including 657 clinically annotated CRC specimens was stained with anti-OX40, -CD8 and -FOXP3 mAbs by standard immunohistochemistry. The CRC cohort was randomly split into training and validation sets. Correlations between CRC infiltration by OX40+ cells alone, or in combination with CD8+ or FOXP3+ cells, and clinical-pathological data and overall survival were comparatively evaluated. OX40 gene expression in CRC significantly correlated with FOXP3 and CD8 gene expression. High CRC infiltration by OX40+ cells was significantly associated with favorable prognosis in training and validation sets in univariate, but not multivariate, Cox regression analysis. CRC with OX40(high)/CD8(high) infiltration were characterized by significantly prolonged overall survival, as compared to tumors with OX40(low)/CD8(high), OX40(high)/CD8(low) or OX40(low)/CD8(low) infiltration in both uni- and multivariate analysis. In contrast, prognostic significance of OX40+ and FOXP3+ cell infiltration was not enhanced by a combined evaluation. Irrespective of TNM stage, CRC with OX40(high)/CD8(high) density infiltrates showed an overall survival similar to that of all stage I CRC included in the study. OX40(high)/CD8(high) density tumor infiltration represents an independent, favorable, prognostic marker in CRC with an overall survival similar to stage I cancers.
Highlights
Colorectal cancer (CRC) represents the second most common cause of cancer-related death [1]
High densities of infiltrating CD8+ T cells are associated with improved disease-free and overall survival in colorectal cancer (CRC) [4,5,6,7,8] and the analysis of tumor infiltration by immune cells has been suggested to outperform the prognostic significance of tumor microarray (TMA) staging [5, 6]
We comparatively addressed OX40 gene expression in CRC tissues and in corresponding healthy mucosa sampled at distance from the tumor (n = 49)
Summary
Colorectal cancer (CRC) represents the second most common cause of cancer-related death [1]. High densities of infiltrating CD8+ T cells are associated with improved disease-free and overall survival in CRC [4,5,6,7,8] and the analysis of tumor infiltration by immune cells has been suggested to outperform the prognostic significance of TMA staging [5, 6]. The expression of activation markers by CRC infiltrating CD8+ T cells has been shown to improve their predictive potential [8]. CRC infiltration by FOXP3+ regulatory T cells (Treg) and myeloid cells was found to be associated with improved prognosis [1012], at difference with a variety of cancers of different histological origin [13, 14]. We explored the prognostic significance of tumor infiltration by OX40+ cells in a large colorectal cancer (CRC) collective
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
