• Largest known analysis of neuroendocrine neoplasms via next-generation sequencing • ANTXR1, encoding for the TEM8 receptor, expression is reliant on tissue of origin • Expression is correlated with increased immune cell presence in all tumors studied • TEM8 is a novel and actionable target in solid tumors The TEM8 receptor (coded by ANTXR1 ) plays several roles in oncogenesis and novel oncolytic therapies, such as the SVV-01 virus, uniquely bind this protein in neuroendocrine tumor (NET) 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). NextGen sequencing of DNA (592 genes or whole exome)/RNA (whole transcriptome) was performed on SCLC (N=1404) and other NET (N=1668) samples submitted to Caris Life Sciences (Phoenix, AZ). Samples were stratified by ANTXR1 expression quartiles (Q1 low, Q4 high). TME cell fractions were estimated by RNA deconvolution using quanTIseq. Real-world overall survival (OS) was assessed from insurance claim data. The landscape of pathogenic gene mutations was similar among ANTXR1 Q1 vs Q4 tumors among SCLC and NET cohorts. The TME of SCLC and NET Q4 tumors comprised a greater fraction of B cells and M1/M2 macrophages and were more frequently classified as ‘T cell-inflamed’ based on a transcriptional signature predictive of response to ICI. However, OS from the start of ICI was similar between ANTXR1 Q1 and Q4 cohorts. Increased B cell and M1/M2 macrophage infiltrate, along with T-cell inflamed status, associated with ANTXR1 Q4 TMEs suggest these patients with SCLC and NET 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.
Kareff et al. (Sun,) studied this question.