Prognostic significance of OX40+ lymphocytes in tumor stroma of surgically resected small-cell lung cancer

Oncoimmunology. 2021 Sep 18;10(1):1971430. doi: 10.1080/2162402X.2021.1971430. eCollection 2021.


OX40 (CD134) is a co-stimulatory molecule mostly expressed on activated T lymphocytes. Previous reports have shown that OX40 can be an immuno-oncology target and a clinical biomarker for cancers of various organs. In this study, we collected formalin-fixed paraffin-embedded tumor samples from 124 patients with small-cell lung cancer (SCLC) who had undergone surgery. We analyzed the expression profiles of OX40 and other relevant molecules, such as CD4, CD8, and Foxp3, in tumor stroma and cancer nest using immunohistochemistry and investigated their association with survival. High infiltration of OX40+ lymphocytes (OX40high) in tumor stroma was positively associated with relapse-free survival (RFS) and overall survival (OS) compared with low infiltration of OX40+ lymphocytes (OX40low) (RFS, median, 26.0 months [95% confidence interval (CI), not reached (NR)-NR] vs 13.2 months [9.1-17.2], p = .024; OS, NR [95% CI, NR-NR] vs 29.8 months [21.3-38.2], p = .049). Multivariate analysis revealed that OX40high in tumor stroma was an independent indicator of prolonged RFS. Moreover, RFS of patients with OX40high/CD4high in tumor stroma was significantly longer than that of patients with OX40low/CD4low. The RFS of patients with tumor stroma with OX40high/CD8high was significantly longer than that of patients with tumor stroma with OX40low/CD8high, OX40high/CD8low, or OX40low/CD8low. These findings suggest that OX40+ lymphocytes in tumor stroma play a complementary role in regulating the relapse of early-stage SCLC. Reinforcing immunity by coordinating the recruitment of OX40+ lymphocytes with CD4+ and CD8+ T cells in tumor stroma may constitute a potential immunotherapeutic strategy for patients with SCLC.

Keywords: CD4; CD8; OX40; Small-cell lung cancer; survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes
  • Humans
  • Lung Neoplasms* / surgery
  • Neoplasm Recurrence, Local
  • Prognosis
  • Small Cell Lung Carcinoma* / surgery

Grants and funding

The analysis in this work was supported by research funding from the Department of Translational Pathology, Hokkaido University Graduate School of Medicine; the Center for Respiratory Diseases, JCHO Hokkaido Hospital; the Department of Pulmonary Medicine, Fukushima Medical University; and the Department of Respiratory Medicine, Hokkaido Cancer Center. The study sponsors did not have any role in the study design, data collection, interpretation of data, writing of the report, and decision to submit this paper for publication. Assistance in English proofreading was paid for by the Department of Respiratory Medicine, Hokkaido Cancer Center.