Breast
Jerica Tidwell, DO
Resident Physician
Department of Surgery, Hospital of the University of Pennsylvania
Philadelphia, United States
Jerica Tidwell, DO
Resident Physician
Department of Surgery, Hospital of the University of Pennsylvania
Philadelphia, United States
Vishnu Maddipatla, BS
Measey Surgical Scholar
University of Pennsylvania, United States
Casey Lam, BS
Research Specialist
University of Pennsylvania, United States
Robert Vonderheide, MD, PhD
Director, Abramson Cancer Center of the University of Pennsylvania
Hospital of the University of Pennsylvania, United States
Jennifer Q. Q. Zhang, MD
Assistant Professor
Division of Breast Surgery, Department of Surgery, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA, United States
Hormone receptor positive (HR+) luminal breast cancer is the most common subtype of breast cancer and patients with locally advanced HR+ disease have poor long-term prognosis. Low rates of pathologic complete response (pCR) are observed after neoadjuvant chemotherapy, thus novel therapies are needed to improve pCR and survival . HR+ breast cancers demonstrate low levels of lymphocyte infiltration and poor response to checkpoint blockade. CD40 stimulation presents as a promising avenue for improving immunogenic response in this cancer subtype. In this study, we investigate the ability of agonistic CD40 therapy to inhibit tumor growth and increase infiltration of cytotoxic CD8 T cells in a murine model of HR+ luminal breast cancer.
Methods:
The Brpkp110 cell line (HR+ luminal breast cancer) was injected orthotopically into the abdominal mammary glands of 8 to 10-week-old C57BL/6 mice and tumors were allowed to establish. Tumor-bearing mice were treated with a single dose of agonistic CD40 antibody (FGK4.5, 100 mg intraperitoneal). Tumors were fixed in zinc formalin and immunofluorescence was performed for CD8 T cells. QuPath software was used to analyze spatial organization of intratumoral CD8 T cells.
Results:
In our murine model of breast cancer, agonistic CD40 had a significant effect on tumor growth inhibition and in a minority of mice, resulted in tumor regressions. This anti-tumor effect was dependent on CD8 T cells, but not CD4 T cells, as demonstrated by CD4 and CD8 depletion studies. Immunofluorescence staining for CD8 T cells demonstrated an increase in intratumoral CD8 T cell infiltration as well as redistribution of CD8 T cells from the periphery into the center of the tumor (Figure 1). These T cells demonstrated increased granzyme B expression. Lastly, agonistic CD40 treated tumors demonstrate increased necrosis with increased staining for the apoptotic marker cleaved caspase-3.
Conclusions:
Our data suggest that agonistic CD40 therapy may be a viable strategy for inhibiting tumor growth and increasing CD8 T cell infiltration. This therapeutic strategy may increase the efficacy of checkpoint blockade and other T cell directed therapies in HR+ luminal breast cancer.