Intratumor heterogeneity is associated with less CD8 T cell infiltration and worse survival in patients with small cell lung cancer.

Purpose: Small cell lung cancer (SCLC) is a heterogeneous malignancy with genetic and phenotypic disparity. However, the association between intratumor heterogeneity (ITH) and immunological features as well as the impact of ITH on prognosis has never been explored in SCLC. Hence, we investigated the relationship between ITH and their immunological features and explored the effect of ITH on overall survival (OS) in patients with SCLC.

Methods: Programmed cell death-ligand 1 (PD-L1), CD8 cell infiltration was calculated through immunohistochemical staining and tumor mutational burden (TMB), tumor neoantigen burden (TNB), and ITH levels via whole-exome sequencing (WES).

Results: Significant correlation was not found in ITH versus TMB, ITH versus TNB (P = 0.1821, P = 0.0612). No significant variation in ITH was found between negative PD-L1 SCLC patients and positive PD-L1 ones (P = 0.0610 for TPS, P = 0.6347 for CPS). Interestingly, we demonstrated the negative correlation between CD8 T cell infiltration and ITH (P = 0.0220). More importantly, significant OS benefit was detected in ITH-low SCLC patients in comparison with ITH-high ones (P = 0.0049). ITH was an independent prognostic factor on OS with clinicopathological variables adjusted (HR, 2.044; 95% CI 1.190-3.512; P = 0.010). We also demonstrated significantly different driver genes and CNV between ITH-low and ITH-high SCLC.

Conclusion: Our work pointed the negative association of ITH with CD8 T cell infiltration and suggested ITH as a potential predictor of OS in SCLC, putting forward a direction for more precise and individualized therapeutic strategies for SCLC.