Abstract 1344: Immune transcriptional profiling in a large animal model of histiocytic sarcoma reveals putative drivers and tumor suppressors

Abstract

Abstract Histiocytic sarcoma (HS) is a rare, yet lethal malignancy with a median overall survival of six months and no universally agreed standard of care therapy. Due to the paucity of human cases, there is a drive to develop model systems to improve our understanding of the pathology underlying this disease and screen new treatment strategies. Spontaneous canine HS exhibits increased prevalence in specific breeds, shares key genetic and biologic similarities with the human disease, and occurs in an immunocompetent setting. Our previous studies revealed a spectrum of hot and cold immune tumor microenvironments (TME) based on tumor infiltrating lymphocyte (TIL) quantification in 18 canine and 5 human HS cases. In dogs, increased TIL densities were positively associated with longer survival times. Despite this association, the disease course of HS in our veterinary patient cohort was nearly uniformly fatal. To evaluate for potential inhibitors of T cell immunity in the TME and identify putative drivers and suppressors of HS, we performed immune transcription profiling. Tumors were selected from 3 short-lived cases of splenic HS that were sparsely infiltrated with TIL and 3 long-lived cases of pulmonary HS that were T cell inflamed. Tumors were compared to corresponding grossly healthy splenic and lung tissues collected from 3 dogs without neoplasia undergoing routine post-mortem examination. RNA was extracted from formalin-fixed paraffin embedded tissues and immune transcription profiling was performed using the NanoString nCounter Canine IO Panel. Analyses of all tumors compared to normal tissues, and subset analyses of tissues stratified based on tissue origin site, revealed enrichment of ITGAX (CD11c) expression in the HS tumor samples consistent with histiocytic origin. In each subset analysis, SPP1 (osteopontin) was highly expressed in HS tumors compared with normal tissues. Osteopontin has been shown to be protumorigenic in a variety of cancers, is a potent chemokine for macrophages, and can suppress T cell activation through ligation of CD44, thus acting as a T cell checkpoint. Additionally, we found decreased expression of TXNIP in HS tumors compared to healthy tissues. TXNIP is an established tumor suppressor gene in various tumor types, including acute myeloid leukemia. Future studies will interrogate the functional implications of these transcriptional changes with the aim of developing novel therapeutic strategies for HS in both species. Citation Format: Jennifer A. Lenz, Charles-Antoine Assenmacher, Enrico Radaelli, Matthew J. Atherton. Immune transcriptional profiling in a large animal model of histiocytic sarcoma reveals putative drivers and tumor suppressors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1344.