Investigation of interleukin-34 dependent regulation of renal carcinoma tumor microenvironment

In 2020, Renal Carcinoma (RC) accounted for around 179,000 worldwide deaths and its mortality is predicted to double in the next 20 years. The major issue for RC patients is the absence of an efficient therapeutic option, especially for metastatic forms of the disease where the 5-years survival rate is close to 10%. The therapy of RC 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 RC progression are main reasons of therapy failure. In our unpublished work, using a syngeneic murine model of RC, we identified interleukin-34 (IL34) as potential biomarker of RC progression. In particular, we observed that increased IL34 expression was associated with enhanced cancer cell aggressiveness and reduced survival both in mice and in RC patients from two different cohorts (i.e. KIRC-TCGA, and UroCCR local cohort). IL34 exerts pleiotropic functions in different biological processes, including immunity regulation, cell proliferation and monocytes survival and differentiation into macrophages. The expression of IL34 in the TME is heterogeneous between cancer types, and high IL34 levels can represent either a poor (i.e. in brain and lung cancers) or a favorable (i.e. in neck and breast cancers) prognostic factor. Regarding to RC, IL34 role in the TME still remains elusive and has never been described. For this reason, using the KIRC-TCGA database, we performed Gene Ontology enrichment analysis using a list of IL34 co-expressed genes to predict potential IL34 regulatory functions in the TME of RC patients. This analysis revealed that such genes are involved in different immune system related processes, including positive regulation of leukocyte activation, IL-10 production and adaptive immune response. Subsequently, using IL34-overexpressing murine renal carcinoma RENCA cells implanted in BALB/c mice, we investigated the IL34-dependent alteration of the tumor immune microenvironment. In particular, we observed that, both in generated primary tumors and lung metastases, IL34 increased the density of tumor associated macrophages (TAM), which expressed M2-type markers (e.g. Cd206 and Cd163). Furthermore, in these samples, qPCR analysis showed an increase of interleukin-10 gene expression suggesting that IL34 could induce an immunosuppressive microenvironment. Conversely, when we blocked IL34 activity in lung metastases using an inhibitor of CSF1R, the main receptor of IL34, we observed a significant reduction in TAM accumulation and Il10 expression. The major aim of this project is to investigate whether IL34 can sustain immunosuppression and, consequently, chemoresistance by accumulating TAM in the TME. Furthermore, the IL34-dependent regulation of other immune cell populations (e.g. T-reg or myeloid-derived suppressor cells) is under investigation. The study of IL34 role in the TME of RC can be fundamental to improve the current therapy. Citation Format: Andrea Emanuelli, Wilfried Souleyreau, Lindsay Cooley, Tiffanie Chouleur, Marie-Alix Derieppe, Jean-Christophe Bernhard, Andreas Bikfalvi. Investigation of interleukin-34 dependent regulation of renal carcinoma tumor microenvironment [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P012.