Molecular subtyping dictates therapeutic response to anti-PD-L1 immunotherapy in ES-SCLC.

Anti-PD-L1 immunotherapy is recommended as standard of care for patients with extensive stage small cell lung cancer (ES-SCLC); however, there are no reliable biomarkers guiding patient selection and the survival benefit of PD-L1 inhibitors in the overall population is limited. In this study, we retrospectively analyzed a total number of 61 cases of ES-SCLC who underwent anti-PD-L1 immunotherapy. Patient demographic characteristics and laboratory findings were processed for univariate and multivariate analysis. Subgrouping of SCLC was performed on IHC platform using antibodies against ASCL1, NEUROD1 and POU2F3. The tumor microenvironment (TME) of ES-SCLC was evaluated by CD8 + T cell infiltration, granzyme B production and PD-L1 expression. We found limited efficacy of defined variable factors conferring therapeutic outcomes of anti-PD-L1 immunotherapy in patients with ES-SCLC. Intriguingly, there was a profound difference in TME and response to anti-PD-L1 immunotherapy when classifying SCLC into A/N/P/I subgroups. Although accounted for a small proportion of SCLC, the SCLC-P and SCLC-I subtypes manifested as T cell-enriched "hot" tumor and elicited more favorable response to immunotherapy, whereas the SCLC-A and SCLC-N subgroups were T cell-absent "cold" tumor. There was also a significant difference in progression free survival and overall survival across these subsets. Moreover, we found the SCLC-P and SCLC-I tumors revealed features of low neuroendocrine (NE) differentiation and showed clinicopathologic features overlapping with the SCLC non-NE lineage. These findings may aid clinicians to select ES-SCLC patients who were more likely to gain higher response rate and longer survival to anti-PD-L1 immunotherapy. Revisiting SCLC according to A/N/P/I subtyping and NE/non-NE differentiation is a reliable approach to guide therapeutic strategy in patients with ES-SCLC.