Abstract 42P
Background
The main challenges for current immunotherapy of triple-negative breast cancer (TNBC) lie in immunosuppressive tumor immune microenvironment (TIME). Considering tumor-associated macrophages (TAMs) are the most abundant immune cells in TIME, resetting TAMs is a promising strategy to ameliorate tumor immunosuppressive microenvironment.
Methods
To explore the potential role of TAMs in TIME of TNBC, we employed immunofluorescence staining of TNBC human tissue microarray chips. Using the TIMER database, we compared different chemokine genes and cytokine genes with various types of immune cells infiltration level. To construct genetically engineered macrophages (GEMs), a novel recombinant adenovirus simultaneously expressing human CXCL9 and IL-12 (Ad5-CXCL9/IL-12) was utilized to infect human and murine macrophages. Additionally, in vitro cytological studies were used to evaluate the anti-tumor phenotype of GEMs and its effects on T cells. Furthermore, in vivo anti-tumor studies and tumor immune microenvironment analysis were performed in immunodeficient and immunocompetent mouse models.
Results
Here, GEMs by gene-carrying adenoviruses were developed to maintain M1-like phenotype and directly deliver immune regulators of IL-12 and CXCL9 into local tumor to reverse immunosuppressive TIME. In tumor bearing mice, GEMs demonstrated a targeted enrichment in tumors and successfully reprogramed TAMs into M1-like macrophages. Meanwhile, GEMs significantly stimulated the accumulation, proliferation and activation of CD8+ T cells, mature dendritic cells (DCs) and natural killer (NK) cells into tumor while reduced M2-like macrophages, immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), thus efficiently suppressed tumor growth. In addition, combination of GEMs and anti-programmed cell death protein 1 (α-PD-1) therapy further improved IFN-γ+CD8+ T cell percentage and tumor inhibition efficacy in an orthotopic murine TNBC model.
Conclusions
Therefore, this study provides a novel strategy to reverse immunosuppressive TIME and improve immunotherapeutic efficacy through live macrophage-mediated gene delivery.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
This project is supported by grants from the National Key Research and Development Plan (2018YFA0900900), the National Natural Science Foundation of China (Grant No. 82473330), Social Development Key Project of Jiangsu Province (No. BE2021629) and Natural Science Key Project of Jiangsu Provincial Education Department (No. 21KJA320009).
Disclosure
All authors have declared no conflicts of interest.