OX40 expression enhances the prognostic significance of CD8 positive lymphocyte infiltration in colorectal cancer
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Benjamin Weixler1, Eleonora Cremonesi2, Roberto Sorge3, Manuele Giuseppe Muraro2, Tarik Delko1, Christian A. Nebiker1, Silvio Däster1, Valeria Governa2, Francesca Amicarella2, Savas D. Soysal1,2, Christoph Kettelhack1, Urs W. von Holzen1,4, Serenella Eppenberger-Castori5, Giulio C. Spagnoli2, Daniel Oertli1, Giandomenica Iezzi2, Luigi Terracciano5, Luigi Tornillo5, Giuseppe Sconocchia6,* and Raoul A. Droeser1,2,*
1 Department of Surgery, University Hospital Basel, Basel, Switzerland
2 Institute of Surgical Research and Hospital Management (ICFS) and Department of Biomedicine, University Hospital Basel, Basel, Switzerland
3 Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
4 IU Health Goshen Center for Cancer Care, Goshen, IN, USA
5 Institute of Pathology, University Hospital Basel, Basel, Switzerland
6 Institute of Translational Pharmacology, National Research Council, Rome, Italy
* These authors have contributed equally to this work
Raoul A. Droeser, email:
Keywords: OX40, CD8, colorectal cancer, prognosis, microenvironment
Received: August 15, 2015 Accepted: September 18, 2015 Published: September 30, 2015
Background: 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.
Methods: 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.
Results: 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 OX40high/CD8high infiltration were characterized by significantly prolonged overall survival, as compared to tumors with OX40low/CD8high, OX40high/CD8low or OX40low/CD8low 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 OX40high/CD8high density infiltrates showed an overall survival similar to that of all stage I CRC included in the study.
Conclusions: OX40high/CD8high density tumor infiltration represents an independent, favorable, prognostic marker in CRC with an overall survival similar to stage I cancers.
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