Analysis of RNA expression of 47 cell surface proteins in real-world small cell lung cancer patients

Small cell lung cancer (SCLC) is an aggressive, smoking-induced bronchogenic lung cancer with few effective treatment options and an abysmal prognosis. Almost all patients relapse after initial induction chemotherapy and immunotherapy, and clinical benefit from subsequent therapies including tarlatamab-dlle (a DLL3 bispecific T cell engager) are limited. Herein, we performed an exploratory analysis of RNA expression of 47 cell surface proteins (CSPs) and 11 selected associated ligands in SCLC patients sequenced with Tempus xT (DNA-seq) and xR (RNA-seq). The CSPs include targets of immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) that are either FDA approved or currently evaluated in clinical trials. CSPs with important roles in modulating the tumor microenvironment (both tumor and stromal cell markers) were also evaluated. Leveraging Tempus dataset's clinical and molecular annotations, we stratified SCLC patients by subtypes (ASCL1, NEUROD1, POU2F3, Inflamed), treatment status (naïve vs. treated), and disease stage (limited vs. extensive). Non-parametric statistical tests (Wilcoxon Rank-Sum Test, Kolmogorov-Smirnov (KS) Test and Anderson-Darling (AD) Test) were applied to uncover robust differential expression patterns across these strata. We interrogated N=1,353 patients for CSP gene expression by subtype. We demonstrate that expression of certain CSPs are enriched in multiple (>2) SCLC subtypes including DLL3 , SEZ6 , CEACAM5 , CD276 and MUC1 . We further identified subtype-specific CSP expression including SSTR2 in NEUROD1 as well as NECTIN4 and ERBB3 in POU2F3. ICI targets including CTLA4 ,  PDCD1 , and  CD274  as well as the ADC target TACSTD2 were increased in Inflamed and to a lesser extent the POU2F3 subtypes. With respect to disease stage, ICI and ADC targets such as CTLA4 , CD274 , PDCD1 , TIGIT , ICOS , TACSTD2 , and MUC1 were significantly (p<0.05) more highly expressed in LS-SCLC (N=210) than in ES-SCLC (N=1,137). With respect to treatment status, we detected significantly (p<0.05) higher expression of CTLA4 , PDCD1 , TIGIT , TACSTD2 , and ITGB6 in treatment-naïve (N=744) than in SCLC patients who had received at least one line of systemic treatment (N=384). Although protein-level validation will be important and should be done when feasible, our exploratory analysis demonstrates that RNA expression of clinically relevant CSPs in SCLC patients may be influenced by subtype classification, cancer stage, and treatment status.