PD-1 blockade elicits a systemic immune response but not in the tumor of TNBC mice

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options due to the absence of hormone receptors and HER2 amplification. Immune checkpoint blockade, particularly targeting PD-1/PD-L1, has emerged as a promising therapeutic strategy. However, the response rate of TNBC patients to this monotherapy remains low. This study explores the systemic effect of PD-1 blockade on the immune and hematopoietic systems in 4T1 TNBC mice and demonstrates its limited efficacy in reducing the tumor burden and changing the number of tumor-infiltrating immune cells. However, PD-1 blockade increases systemic immune activity, as demonstrated by increased T cells and DCs in the peripheral blood, which may be associated with inflammatory side effects of this treatment. In addition, PD-1 blockade does not rescue the hematopoietic damage caused by TNBC, highlighting a limitation in long-term response. Furthermore, PD-1 blockade in tumor-free mice leads to an increase in hematopoietic stem/progenitor cells, suggesting that PD-1 blockade may yield better benefits post-tumor resection.

1. Introduction

Triple-negative breast cancer (TNBC) is a breast cancer (BC) subtype characterized by high recurrence and mortality rates [1]. TNBC patients rarely benefit from targeted therapies because of the absence of human epidermal growth factor receptor 2 (HER2) amplification and estrogen receptor (ER) and progesterone receptor (PR) expressions. Therefore, chemotherapy remains the primary adjuvant therapy for TNBC, despite the development of drug resistance leading to disease relapse and metastasis [2,3]. Immune checkpoint blockade, particularly targeting PD-1 (programmed cell death protein-1)/PD-L1 (programmed cell death ligand-1), has emerged as a promising treatment for TNBC.

PD-1 is an essential immune checkpoint receptor that, when bound to the ligand PD-L1, hinders T-cell activation. Tumor cells express PD-L1 to evade immune surveillance and suppress T-cell function [4]. TNBC, characterized by high levels of PD-L1 expression and tumor-infiltrating lymphocytes (TILs), is a promising candidate for PD-1/PD-L1 blockade therapy [5–7]. However, the response rate of TNBC patients to monotherapy is limited, promoting research into combination therapies to improve treatment efficacy [8–11]. Studies on immune checkpoint blockade have focused on the tumor microenvironment (TME), where immune cells play a crucial role in treatment effectiveness [12]. Immunosuppressive cells such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and T regulatory (Treg) cells support tumor growth, whereas cytotoxic T cells and natural killer (NK) cells work to eliminate tumor cells [13,14]. Dendritic cells (DCs), T helper cells, and B cells assist or regulate antitumor immunity [15].