Immune Checkpoints OX40 and OX40L in Small-Cell Lung Cancer: Predict Prognosis and Modulate Immune Microenvironment

Peixin Chen; Hao Wang; Lishu Zhao; Haoyue Guo; Liping Zhang; Wei Zhang; Chenglong Sun; Sha Zhao; Wei Li; Jun Zhu; Jia Yu; Chunyan Wu; Yayi He

doi:10.3389/fonc.2021.713853

Immune Checkpoints OX40 and OX40L in Small-Cell Lung Cancer: Predict Prognosis and Modulate Immune Microenvironment

Front Oncol. 2021 Nov 25:11:713853. doi: 10.3389/fonc.2021.713853. eCollection 2021.

Authors

Peixin Chen^{1

2}, Hao Wang^{1

2}, Lishu Zhao^{1

2}, Haoyue Guo^{1

2}, Liping Zhang³, Wei Zhang³, Chenglong Sun^{1

4}, Sha Zhao^{1

2}, Wei Li^{1

2}, Jun Zhu^{1

2}, Jia Yu^{1

2}, Chunyan Wu³, Yayi He^{1

2}

Affiliations

¹ School of Medicine, Tongji University, Shanghai, China.
² Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
³ Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
⁴ Anhui No. 2 Provincial People's Hospital, Hefei, China.

Abstract

Background: OX40 and OX40 ligand (OX40L), as essential immune checkpoint (IC) modulators, are highly correlated with cancer immunity regulation as well as tumor microenvironment (TME). Immunotherapy showed outstanding advantages in small-cell lung cancer (SCLC) therapy. However, functions and clinical significance of OX40 and OX40L in SCLC were not clear yet.

Materials and methods: SCLC samples of 143 patients were collected for immunohistochemistry (IHC) or whole-exome sequencing (WES). We comprehensively explored the expression and mutation of OX40/OX40L in SCLC, and systematically linked OX40/OX40L with TME.

Results: The expression of OX40/OX40L on tumor cells and tumor-infiltrating lymphocytes (TILs) was found in the IHC cohort and verified in other cohorts with SCLC tissues and cell lines. The results showed co-expression patterns among OX40/OX40L, other ICs, and T-cell markers. The WES data suggested that OX40/OX40L mutation is rare in SCLC (<5%). Patients with positive OX40 protein expression on TILs showed substantially higher recurrence-free survival than those with negative expression (p=0.009). The external dataset also indicated that high OX40/OX40L expression was correlated with better prognosis [overall survival: OX40, p<0.001; OX40L, p=0.019]. Importantly, activation of immunity and high infiltration of CD4(+) and CD8(+) T cells were observed in the high OX40/OX40L expression group.

Conclusions: Collectively, this work highlighted the significance of OX40 and OX40L in prognosis and TME cell infiltration characterization of SCLC. Evaluating the OX40/OX40L-expression levels of individual patients with SCLC might contribute to guiding more precise therapy.

Keywords: OX40 (CD134); OX40 ligand; prognosis; small cell lung cancer; tumor immune microenvironment.