Abstract 3637: Extracellular matrix drives high-grade breast cancer immune suppression down-modulating PD-1 on Treg cells via the IL-23/SATB1 axis
Authors: Talarico Giovanna , Lecchi Mara , Costanza Massimo , Chiodoni Claudia , Cappelletti Vera , Verderio Paolo , Nicola Massimo Di , Bertolini Francesco , Colombo Mario Paolo , Sangaletti Sabina 
Published: June 2023

Abstract
The pathological grade defines tumor aggressiveness and, indeed, high-grade breast cancer (HGBC), regardless of molecular findings, is characterized by a very aggressive clinical course and a poor prognosis in spite of the availability of chemotherapy regimens and specific-targeted agents. Both the cellular and the extracellular compartments of the tumor microenvironment (TME) can contribute to the evolution of BC by immune escape and immune suppression processes. In this context, structural and extracellular components of the TME, namely the extracellular matrix (ECM), has been shown to contribute to many aspects of tumor progression, exerting important regulatory functions on tumor cells. The relevance of the ECM in cancer progression is strengthened by study showing that the ECM composition is a prognostic factor able to identify patients subgroups endowed with a different clinical outcome according to the distinct enrichment in ECM genes leading to four specific ECM signatures (ECM 1-4). Among the different ECM-related signatures, only the ECM3 signature - characterizing about 35 % of HGBC - identifies the most aggressive tumors with epithelial mesenchymal transition (EMT) features, poor prognosis, T-cell exclusion and an increased infiltration of myeloid-derived suppressor cells (MDSCs). To evaluate whether local immune suppressive features of ECM3+ tumors can be intercepted in the peripheral blood (PB), to represent a potential biomarker for this subset of tumors, we collected consecutive HGBC patients that included 22 ECM3+ and 30 ECM3- and performed a multiparametric flow cytometry analysis. We found PD-1neg Treg being correlated to ECM3 patients and through ad hoc mouse BC models, we provided the mechanisms through which SPARC, a key functional gene of the ECM3 signature, was responsible for the down-modulation of PD-1 on Treg, positively affecting their suppressive activity. By sustaining the release of IL-23, SPARC promotes SATB1 expression that repress PD-1. Notably, fluvastatin treatment in vivo decreased the expression of SATB1 in treated Treg cells, a result paralleled by an increased expression of PD-1 on Treg cells. Our data extend the regulatory activity of the extracellular matrix and SPARC, which are large characterized for myeloid cells, to regulatory T-cells also offering new possible targets for the treatment of high-grade breast tumors.
Citation Format: Giovanna Talarico, Mara Lecchi, Massimo Costanza, Claudia Chiodoni, Vera Cappelletti, Paolo Verderio, Massimo Di Nicola, Francesco Bertolini, Mario Paolo Colombo, Sabina Sangaletti. Extracellular matrix drives high-grade breast cancer immune suppression down-modulating PD-1 on Treg cells via the IL-23/SATB1 axis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3637.