Abstract 3140: Interleukin-34 regulates tumor immune microenvironment of renal cell carcinoma

Abstract Renal Cell Carcinoma (RCC) is a type of kidney cancer which derives from renal tubular epithelial cells and is responsible for approximately 90-95% of cases in adults. Incidence and prevalence of RCC are rising, and 5-year survival of metastatic disease is close to 10%. The therapy of RCC mainly targets the angiogenic and immunosuppressive tumor microenvironment (TME), but it is rarely curative and drug resistance is almost inevitable. Lack of validated biomarkers and scarce knowledge of the biological processes occurring during RCC progression are main reasons of therapy failure. Using an immunocompetent murine model of RCC, we identified Interleukin-34 (IL34) as potential biomarker of RCC progression, whose expression is associated with advanced tumor stage and reduced survival in RCC patients. In cancer, IL34 was demonstrated to regulate cancer cell proliferation and monocytes survival and differentiation into macrophages. Regarding to RCC, IL34 role in the TME still remains elusive and has never been described. To elucidate the function of IL34 in RCC biology, we undertook different approaches: Gene Ontology enrichment analysis of IL34 co-expressed genes, using the KIRC-TCGA database, which revealed that such genes are involved in different immune system related processes; orthotopic implantation of IL34 over-expressing murine renal cancer cells (i.e. RENCA cell line) in BALB/c mice, where we observed, both in primary tumors and lung metastases, an accumulation of tumor associated macrophages (TAM) expressing M2-type macrophage markers (e.g. Cd206 and Cd163). Subsequently, to deeply investigate how IL34 can finely tune the tumor immune microenvironment of RCC, we also employed an experiment of Single Nuclei Sequencing using murine samples over-expressing IL34 (or control empty vector). Briefly, RENCA cancer cells were implanted in BALB/c mice using two different injection modalities: orthotopic implantation in the kidney, to generate primary tumors; 2) tail vein injection, for lung metastases formation. After tumor or metastases formation, samples were snap-frozen in liquid nitrogen and processed for cDNA library preparation for next generation sequencing. Our project aims to elucidate how IL34 can be implicated in the regulation of TME in RCC and, in particular, of the phenotype of the accumulated TAM. As TAM are known to promote cancer progression by enhancing tumor angiogenesis and immunosuppression, the study of IL34 role in the TME can reveal novel paradigms in RCC biology, and may be fundamental to improve the current therapy (e.g. using drugs targeting IL34 activity). Citation Format: Andrea Emanuelli, Wilfried Souleyreau, Tiffanie Chouleur, Marie-Alix Derieppe, Andreas Bikfalvi. Interleukin-34 regulates tumor immune microenvironment of renal cell carcinoma [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 3140.