Splenic immunomodulatory effects of cisplatin in an immunocompetent intraductal model for triple-negative breast cancer

Chemotherapy remains the mainstay treatment for aggressive breast cancer subtypes such as triple-negative breast cancer (TNBC). It has been recognized that some chemotherapeutics besides being cytotoxic to tumor cells, also induce immunomodulatory effects that can stimulate tumor cell killing. We aimed to in-depth investigate this presumed chemotherapy-induced immunomodulation in TNBC, focusing on the platinum-based agent cisplatin and using an in-house characterized immunocompetent intraductal mouse model. Our model relies on the injection of 4T1 triple-negative mammary tumor cells in syngeneic lactating mice, representing TNBC progression from early ductal carcinoma in situ/DCIS to late invasive carcinoma/IC stages. As soon as primary tumors transitioned from DCIS to IC, cisplatin treatment was provided and induced significant reduction in disease progression as corroborated by decreased serum levels of immune-related metastatic biomarkers chitinase 3-like 1 and lipocalin 2. After 3 weeks of treatment, primary tumors, metastases-bearing organs (i.e., axillary lymph nodes and lungs), spleen and blood were isolated for flow cytometric immunophenotyping and expression of immune checkpoint proteins programmed death (PD)-1 and PD-ligand (L)1. Immunosuppressive myeloid cells, most abundantly CD11b+Ly6C-Ly6G+ granulocytic myeloid-derived suppressor cells, accumulated in all investigated compartments and were significantly reduced by cisplatin treatment in axillary lymph nodes and spleen. In contrast to the axillary lymph nodes, cisplatin-treated spleens showed enhanced content of CD3ε+CD4+CD8α- helper T cells, CD3ε+CD4-CD8α+ cytotoxic T cells and CD19+ B cells. Cisplatin-treated spleens also showed significant increased PD-(L)1 expression. These results highlight spatial immunomodulatory differences and suggest significant splenic support of anti-tumor immunity upon cisplatin treatment in our TNBC model