Using syngeneic murine TNBC models (4T1, EMT6, and E0771), Gao et al. assessed the antitumor effects of carboplatin and anti-PD-1 antibody in a neoadjuvant setting. Treatment of primary tumors with carboplatin and anti-PD-1 antibodies as neoadjuvant therapy led to a sustained antitumor effect and prolonged survival following secondary tumor challenge after surgery, and increased infiltration of CD8+ T cells, memory T cells, CCL4, and CD103+ dendritic cells into the challenge tumor. The antitumor effect of the combination was reliant on CD8+ T cell function and CCL4-mediated CD103+ DC and CD8+ T cell recruitment.
Contributed by Shishir Pant
ABSTRACT: Patients with triple-negative breast cancer (TNBC) suffer an unfavorable prognosis. Carboplatin (CBDCA) as a cytotoxic reagent has been widely administered to patients with cancer including TNBC. Programmed cell death protein 1 (PD-1) is an immune checkpoint, blockade of which unleashes T cell functions that kill cancer cells. However, the efficacy of CBDCA combined with anti-PD-1 antibodies in TNBC has not been determined. Patient-derived xenografts (PDX) were implanted to immune-deficient mice. Three mouse TNBC cell lines (4T1, EMT6, and E0771) were seeded to immune-competent mice. Tumor volumes and survival rates were monitored. CBDCA and anti-PD-1 antibodies were administered by intra-peritoneal injection at designated time points. Total CD8(+) T cells, memory CD8(+) T cells, and CD103(+) dendritic cells (DC) in the tumor were measured by flow cytometry. Tumor-specific CD8(+) T cells were quantified by the ELISpot assay. Administration of CBDCA to PDX-bearing mice induced increased levels of tumor cell necrosis and reduced tumor size. Treatment with CBDCA and anti-PD-1 antibodies reduced TNBC tumor volumes and slightly improved survival rates. More importantly, therapy with CBDCA and anti-PD-1 antibodies before surgery showed a remarkably improved, sustainable protection against a secondary tumor after surgery by a CD8(+)- T-cell-dependent manner, which required CCL4 expressed in the tumor and subsequently CD103(+) DC recruited to the tumor microenvironment. Immunochemotherapy with CBDCA and anti-PD-1 antibodies before surgery improves the outcome of a secondary tumor after surgery via increasing the number of tumor-specific CD8(+) T cells in the tumor microenvironment of murine TNBC. These results highlight the possibility to utilize this regimen in clinical practice.
Author Info: (1) Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China. (2) Department of Gastrointestinal Surgery, Harbin Medical University Can
Author Info: (1) Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China. (2) Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, China. (3) Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China. (4) Department of Internal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China. (5) Department of Medical Education, First Affiliated Hospital of Harbin Medical University, Harbin, China. (6) Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
