OX40 expression enhances the prognostic significance of CD8 positive lymphocyte infiltration in colorectal cancer.

Abstract

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 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.

CONCLUSIONS:

OX40(high)/CD8(high) density tumor infiltration represents an independent, favorable, prognostic marker in CRC with an overall survival similar to stage I cancers.

• Authors: Benjamin Weixler, Eleonora Cremonesi, Roberto Sorge, Manuele Giuseppe Muraro, Tarik Delko, Christian A Nebiker, Silvio Däster, Valeria Governa, Francesca Amicarella, Savas D Soysal, Christoph Kettelhack, Urs W von Holzen, Serenella Eppenberger-Castori, Giulio C Spagnoli, Daniel Oertli, Giandomenica Iezzi, Luigi Terracciano, Luigi Tornillo, Giuseppe Sconocchia, Raoul A Droeser
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 35 Pg. 37588-99 (Nov 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26439988 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• CD8 Antigens
• FOXP3 protein, human
• Forkhead Transcription Factors
• RNA, Messenger
• Receptors, OX40
• TNFRSF4 protein, human

Topics

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor (genetics, metabolism)
• CD8 Antigens (genetics, metabolism)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Colorectal Neoplasms (genetics, immunology, metabolism, mortality)
• Female
• Follow-Up Studies
• Forkhead Transcription Factors (genetics, metabolism)
• Humans
• Immunoenzyme Techniques
• Lymphocytes, Tumor-Infiltrating (immunology, metabolism)
• Male
• Middle Aged
• Neoplasm Grading
• Neoplasm Staging
• Prognosis
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Receptors, OX40 (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Rate
• Tissue Array Analysis