Targeting CD38 May Enhance Chemotherapy Efficacy in Small Cell Lung Cancer

Targeting CD38 may significantly enhance the efficacy of chemotherapy in patients with small cell lung cancer (SCLC), according to study results published in Frontiers in Immunology.

CD38 is widely expressed in both hematopoietic and non-hematopoietic cells. It has previously been associated with immune suppression in cancer, including its role in enabling tumor escape from immune checkpoint blockade therapies targeting programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC). 

“In this study, we explored the landscape of CD38 in tumors in patients with SCLC and the effect of CD38 blockade and platinum chemotherapy treatment, with or without PD-L1 blockade in SCLC models,” explained Hirokazu Taniguchi, Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences in Nagasaki, Japan, Department of Medicine, Memorial Sloan Kettering Cancer Center in New York, NY, United States, and coauthors. “This is the first study investigating the role of CD38 in anti-tumor immunity of SCLC,” they added.

Key findings revealed that CD38 is highly expressed in SCLC, particularly on immune cells like CD8+ T cells and regulatory T cells. The frequency of CD38 expression on CD8+ T cells was significantly higher in treatment-naïve SCLC samples compared to normal tissues and treatment-naïve lung adenocarcinoma, indicating an immune-suppressed phenotype. In fact, CD38 expression was positively correlated with immunosuppressive markers such as FOXP3, CTLA-4, and PD-1.

Anti–PD-L1 treatment was found to upregulate CD38 expression in SCLC models. In the RPM mouse model, which closely resembles human disease, CD38 ribonucleic acid (RNA) expression increased significantly following anti–PD-L1 treatment, as confirmed by bulk RNA sequencing and real-time polymerase chain reaction (PCR) analysis.

The study also demonstrated that chemotherapy further induces CD38 expression, suggesting that CD38 could serve as a biomarker for chemotherapy resistance in SCLC. Flow cytometry analysis showed that post-chemotherapy samples exhibited significantly higher CD38 expression on CD4+ and CD8+ T cells than treatment-naïve samples.
In preclinical models, concomitant blockade of CD38 and PD-L1, combined with chemotherapy agents cisplatin and etoposide, resulted in a significant delay in tumor growth. Specifically, the combination treatment delayed tumor growth by approximately 25% compared to chemotherapy alone (P = .055).

“Treatment with chemotherapy and [immune checkpoint blockade] enhances the expression CD38 on T cells, suggesting that the addition of CD38 blockade may have the potential to augment the efficacy of chemotherapy and PD-L1 blockade in SCLC,” concluded the study authors.

Reference
Taniguchi H, Chavan SS, Chow A, et al. Role of CD38 in anti-tumor immunity of small cell lung cancer. Front Immunol. 2024;15:1348982. doi:10.3389/fimmu.2024.1348982