Abstract Lung cancer is the leading cause of cancer-related mortality. Small-cell lung cancer (SCLC), accounting for about 10-15% of lung cancer diagnoses, is an exceptionally lethal subtype. Due to rapid growth, early metastasis, and resistance to therapy, SCLC often causes patient death within months. Standard first-line platinum-etoposide (PE) therapy shows significant effects and high response rates. However, recurrence is nearly inevitable, and recurrent tumors are often resistant to further treatment. Recently, combination treatments incorporating an anti-PD-L1 antibody (either atezolizumab or durvalumab) alongside PE therapy have significantly improved survival rates compared to standard PE treatment alone in SCLC patients. However, in contrast to non-small cell lung cancer (NSCLC), other immune checkpoint inhibitors (ICIs), including anti-PD-1 combined with PE, have not shown survival benefits in SCLC. The reason why only anti-PD-L1 demonstrate in SCLC remains unclear and requires further investigation. Furthermore, unlike in other cancers, the efficacy of anti-PD-L1 in SCLC is not correlated with PD-L1 expression on the cell membrane. The selective efficacy of anti-PD-L1 in SCLC suggests that it may function through a distinct mechanism of action, independent of the traditional T cell-dependent pathway. Our previous study found that PD-L1 operates in a cancer cell-intrinsic manner, independent of the interaction with PD-1. Based on these results, we hypothesize that non-membranous intracellular PD-L1 contributes to cancer cell-intrinsic PD-L1 functions and is associated with tumor progression. To test this hypothesis, we performed immunocytochemistry (IHC) and immunofluorescence (ICC) on SCLC specimens from patients at various disease stages and on SCLC cell lines. Our analyses revealed that membranous PD-L1 was rarely detected in SCLC cells in culture or in patient specimens. Instead, PD-L1 expression was predominantly found in the cytoplasm and nucleus of SCLC tumor cells. Among 72 SCLC samples, 59 cases (82%) exhibited cytoplasmic PD-L1, 10 cases (14%) displayed nuclear PD-L1, while only 6 cases (8%) showed membranous PD-L1 expression. We observed a trend toward increased cytoplasmic PD-L1 prevalence and intensity in stage II and III SCLC tumors compared with stage I tumors. In contrast, membranous PD-L1 was readily detected on the cell membrane of most NSCLC tumor cells. Despite the minimal membranous PD-L1 expression, anti-PD-L1 durvalumab significantly increased cisplatin cytotoxicity in SCLC cells independent of T cells. Our findings suggest that intracellular, rather than membranous, PD-L1 plays a key role in SCLC progression. Further studies on its functions and mechanisms may guide the development of more effective SCLC therapies. Citation Format: Ji Young Lee, Anindita Das, HyeonJoo Cheon, . Cytoplasmic PD-L1 levels are associated with tumor progression in small cell lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2815.
Lee et al. (Fri,) studied this question.