The genomic, transcriptomic, and immunologic landscape of TEM8 (ANTXR1) in small-cell lung cancer (SCLC).

Abstract

3128 Background: The TEM8 receptor (coded by ANTXR1) plays several roles in oncogenesis. Novel oncolytic therapies, such as the SVV-01 virus, uniquely bind this protein in tumor histologies such as small-cell lung cancer (SCLC). Emerging pre-clinical data suggest that TEM8-targeting therapies may convert immunologically “cold” tumor microenvironments (TME) into “hot” milieu with greater responses to immune checkpoint inhibitors (ICIs). Methods: NextGen sequencing of DNA (592 genes or whole exome)/RNA (whole transcriptome) was performed on SCLC ( N=1404) submitted to Caris Life Sciences (Phoenix, AZ). Mutations were defined as pathogenic SNVs/indels. ANTXR1H and ANTXR1L samples included those with >75th and <25th percentile expression, respectively. PD-L1 expression (22c3; Positive (+):TPS ³1%) was assessed by IHC. High tumor mutational burden (TMB-H) was defined as ≥10 mutations per MB. Cell infiltration in the TME was estimated by QuantiSEQ. Gene expression profiles were analyzed for transcriptional signatures predictive of response to immunotherapy (T cell-inflamed) and MAPK pathway activation score (MPAS). Real-world median overall survival (mOS) was assessed from insurance claims data, and Kaplan-Meier estimates were calculated for molecularly defined subpopulations of patients. Mann-Whitney U and X2/Fisher-Exact tests were applied where appropriate, with P-values adjusted for multiple comparisons ( p<0.05). Results: No pathogenic mutations were significantly associated with ANTXR1H vs L tumors ( p>0.05 for all), along with no differences in the prevalence of TMB-H (28.6% vs 36.3%, p=1) or PDL1+ (45.0%: vs 35.0%, p=1). However, a greater proportion of B cells (6.53 % vs 5.12%, p<0.001), M1 (1.63% vs 0.37%, p<0.001) and M2 macrophages (3.40% vs 1.50%, p<0.001) were observed in ANTXR1H TME, which were more frequently classified as T cell-inflamed compared to ANTXR1L TME (23% vs 5%, p<0.001). ANTXR1H tumors also had higher MPAS compared to ANTXR1L (1.36 vs -1.86 arbitrary units, p<0.001). There was no significant difference in mOS between ANTXR1H vs L tumors (12.2 vs 10.5 months, HR: 0.95, p=0.678). Conclusions: Increased B cell, M1 and M2 macrophage infiltrates, and increased prevalence of T-cell inflamed tumors in ANTXR1H TME suggest that these patients with SCLC may respond preferentially to ICI. A Phase 1 trial incorporating SVV-01 along with ICI is underway. Prospective investigation of molecular associations and clinical outcomes related to ANTXR1 expression in SCLC is warranted.