Abstract
Abstract Introduction: TEM8 (coded by ANTXR1) is overexpressed in malignant tissues, with oncolytic viruses such as SVV-01 uniquely binding to this receptor on tumor-associated angiogenic endothelial cells, pericytes, fibroblasts, and immune inflammatory cells. Recent pre-clinical data suggest that TEM8-targeting therapies may convert immunologically “cold” tumor microenvironments (TME) into “hot” milieu more amenable to treatment with immune checkpoint inhibitors (ICIs). Methods: NextGen sequencing of DNA (592 genes or WES) and RNA (WTS) was performed on neuroendocrine neoplasms (NENs; N = 1724), excluding small-cell lung cancer, submitted to Caris Life Sciences (Phoenix, AZ). Mutations were defined as pathogenic SNVs/indels. ANTXR1 expression was divided by ANTXR1-expression quartiles (transcripts per million [TPM];Q4:H;Q1:L). PD-L1 expression (SP142; Positive (+): ≥2+,≥%5) 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). Overall survival (OS) data was obtained from insurance claims, 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: NENs from the adrenal gland had the highest median ANTXR1 expression (50 TPM), followed by those from the colon and rectum (43.5), genitourinary organs (43.3), and small bowel (excluding appendix) (39.2). The lowest median ANTXR1 expression was observed in NENs from the pancreas (31.5). 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 (8.6% vs 12.6%, p=1) or PD-L1+ (5.8%: vs 3.1%, p=1). A greater proportion of B cells (5.34 % vs 3.78%, p<0.001), M1 (1.46% vs 0.15%, p<0.001) and M2 macrophages (3.92% vs 2.67%, p<0.001), and T-regulatory cells (1.77% vs 1.08%, p<0.001) was observed in ANTXR1H TMEs, which were more frequently classified as T cell-inflamed compared to ANTXR1L (42% vs 8%, p<0.001). ANTXR1H tumors also had higher MPAS compared to ANTXR1L (1.16 vs -1.61 arbitrary units, p<0.001). There was no significant difference in median OS between ANTXR1H vs L tumors (18.8 mo. vs 21.2 months, Hazard Ratio:1.18, p=0.114). Conclusion: The increased immune cell infiltrate and prevalence of T-cell inflamed status among ANTXR1H NENs suggests these tumors might be more responsive to treatment with ICIs. As trials incorporating intratumoral injections of SVV-01 in combination with ICIs are underway, further investigation of clinical and molecular associations with ANTXR1 expression in NENs is warranted. Citation Format: Samuel A. Kareff, Harris Krause, Andrew Elliott, Peter Hosein, Emil Lou, Heloisa Soares, Matthew Oberley, Aman Chauhan. The genomic, transcriptomic, and immunologic landscape of TEM8 (ANTXR1) in neuroendocrine neoplasms (NENs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6851.