Abstract PR03: CSF-1R antibody targeting therapy with combined metronomic chemotherapy and immune checkpoint blockade enhance a B and T cell response to attenuate metastatic triple negative breast cancer
Authors: Diego A Pedroza, Qian Zhu, Weigou Wu, Paul Porter, Xiang H-F Zhang, Jeffrey M Rosen
Journal: Cancer Research (2024)

Abstract Background: Increased macrophage infiltration and elevated levels of Epithelial to Mesenchymal Transition (EMT) gene signatures are associated with a poor outcome following neo-adjuvant chemotherapy in patients with triple negative breast cancer (TNBC). Further, metastatic disease with overall the poorest survival rates has a cold tumor immune microenvironment (TIME), especially in lung and liver metastases. Interestingly, an abundance of macrophages are observed at these metastatic sites. We have extensively characterized multiple preclinical syngeneic Trp53-/- tumor models that have extensive Tumor Associated Macrophage (TAM) infiltration. These tumor models transcriptionally resemble “claudin-low”, “basal-like” and “luminal-like” breast cancers. From these models the “claudin-low” closely phenocopy the high EMT/TAM subtype observed in patients. Objective: Accordingly, we asked if SNDX-ms6352 a novel specific, high affinity monoclonal antibody targeting CSF-1R in combination with Chemotherapy (CTX) and immune checkpoint blockade might provide an alternative approach for treating established lung and liver metastases. Methods: Single cells from primary T12 mammary tumors were introduced either via tail vein injection to obtain lung metastases or portal vein (PV) injection for liver metastases. Mice were injected with BrdU and multiple lung and liver tissues are harvested randomly to identify established metastases. The mice were randomized into treatment groups and administered four weekly treatments of IgG, CTX, SNDX-ms6352, CTX+SNDX-ms6352 or CTX+SNDX-ms6352+aPD1. Tissues were harvested and fixed overnight in 4% PFA then placed in 70% EtOH for paraffin embedding and stained for H&amp;E, Immunohistochemistry (IHC), Immunofluorescence (IF) and Imaging Mass Cytometry (IMC). Results: Following four weekly treatments of IgG, SNDX-ms6352 and CTX+/-SNDX-ms6352 we observed a decrease in lung metastatic burden and an increase in overall survival as compared to IgG, CTX and SNDX-ms6352 alone. Interestingly we also observed increased CD8 T-cell infiltration, but only in the combination treated mice 28 and 56 days post treatment. However, lung metastases recurred in all of the mice several weeks later. Data from IMC showed intra-tumoral heterogeneity with increased PD-L1 and Ki67. Short term treated lung and liver metastases with the addition of aPD1 demonstrated increased CD20+ B and CD8+ T cell expansion and cleared most of the lung and liver metastatic burden. These results suggest that targeting macrophages enhances the immunostimulatory effect of metronomic CTX with immune checkpoint blockade in treating not only primary tumors, but also established lung and liver metastases via the activation of the tumor immune microenvironment. Supported by R01CA148761-12 and American Cancer Society – AutoZone Breast Cancer Postdoctoral Fellowship, PF-22-163-01-MM grants. Citation Format: Diego A Pedroza, Qian Zhu, Weigou Wu, Paul Porter, Xiang H-F Zhang, Jeffrey M Rosen. CSF-1R antibody targeting therapy with combined metronomic chemotherapy and immune checkpoint blockade enhance a B and T cell response to attenuate metastatic triple negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr PR03.