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

Hiroshi Yokouchi; Hiroshi Nishihara; Toshiyuki Harada; Toraji Amano; Takayuki Ohkuri; Shigeo Yamazaki; Hajime Kikuchi; Satoshi Oizumi; Hidetaka Uramoto; Fumihiro Tanaka; Masao Harada; Kenji Akie; Fumiko Sugaya; Yuka Fujita; Kei Takamura; Tetsuya Kojima; Mitsunori Higuchi; Osamu Honjo; Yoshinori Minami; Naomi Watanabe; Masaharu Nishimura; Hiroyuki Suzuki; Hirotoshi Dosaka-Akita; Hiroshi Isobe

doi:10.1080/2162402X.2021.1971430

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.

Authors

Hiroshi Yokouchi^{1

2}, Hiroshi Nishihara^{3

4}, Toshiyuki Harada⁵, Toraji Amano⁶, Takayuki Ohkuri⁷, Shigeo Yamazaki⁸, Hajime Kikuchi^{9

10}, Satoshi Oizumi², Hidetaka Uramoto^{11

12}, Fumihiro Tanaka¹¹, Masao Harada², Kenji Akie¹³, Fumiko Sugaya¹⁴, Yuka Fujita¹⁵, Kei Takamura¹⁰, Tetsuya Kojima¹⁶, Mitsunori Higuchi^{17

18}, Osamu Honjo^{19

20}, Yoshinori Minami²¹, Naomi Watanabe²², Masaharu Nishimura⁹, Hiroyuki Suzuki²³, Hirotoshi Dosaka-Akita²⁴, Hiroshi Isobe¹⁶

Affiliations

¹ Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan.
² Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan.
³ Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
⁴ Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan.
⁵ Center for Respiratory Diseases, JCHO Hokkaido Hospital, Sapporo, Japan.
⁶ Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Sapporo, Japan.
⁷ Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
⁸ Department of Thoracic Surgery, Keiyukai Sapporo Hospital, Sapporo, Japan.
⁹ First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
¹⁰ Department of Respiratory Medicine, Obihiro-Kosei General Hospital, Obihiro, Japan.
¹¹ Second Department of Surgery, University of Occupational and Environmental Health, Kita-kyushu, Japan.
¹² Department of Thoracic Surgery, Kanazawa Medical University, Uchinada, Japan.
¹³ Department of Respiratory Disease, Sapporo City General Hospital, Sapporo, Japan.
¹⁴ Department of Respiratory Medicine, Teine Keijinkai Hospital, Sapporo, Japan.
¹⁵ Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, Asahikawa, Japan.
¹⁶ Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo, Japan.
¹⁷ Department of Thoracic Surgery, Fukushima Red Cross Hospital, Fukushima, Japan.
¹⁸ Department of Thoracic Surgery, Aizu Medical Center, Aizuwakamatsu, Japan.
¹⁹ Department of Respiratory Medicine, Sapporo-Kosei General Hospital, Sapporo, Japan.
²⁰ Department of Respiratory Medicine, Sapporo Minami Sanjo Hospital, Sapporo, Japan.
²¹ Respiratory Center, Asahikawa Medical University, Asahikawa, Japan.
²² Department of Internal Medicine, Sunagawa City Medical Center, Sunagawa, Japan.
²³ Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan.
²⁴ Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Abstract

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 (OX40^high) in tumor stroma was positively associated with relapse-free survival (RFS) and overall survival (OS) compared with low infiltration of OX40⁺ lymphocytes (OX40^low) (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 OX40^high in tumor stroma was an independent indicator of prolonged RFS. Moreover, RFS of patients with OX40^high/CD4^high in tumor stroma was significantly longer than that of patients with OX40^low/CD4^low. The RFS of patients with tumor stroma with OX40^high/CD8^high was significantly longer than that of patients with tumor stroma with OX40^low/CD8^high, OX40^high/CD8^low, or OX40^low/CD8^low. 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.