Combination Immunotherapy with Cytotoxic T-Lymphocyte–Associated Antigen-4 and Programmed Death Protein-1 Inhibitors Prevents Postoperative Breast Tumor Recurrence and Metastasis

Abstract

Postoperative tumor recurrence and metastasis remain an extreme challenge in breast cancer. Therapies that target cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have provided unprecedented clinical benefits in various types of cancer. The aim of this study was to determine whether the combination of anti-CTLA-4 and anti-PD-1 could prevent postoperative breast tumor recurrence and metastasis in breast tumor-bearing mice. The results indicated that the combination of CTLA-4 and PD-1 inhibitors was more effective compared with single inhibitors for mammary tumor growth and prevention of postsurgical tumor recurrence and pulmonary metastasis (<i>P</i> < 0.05), which resulted in prolonged survival (<i>P</i> < 0.05). Analysis of the underlying mechanism revealed that anti-CTLA-4 and anti-PD-1 in combination synergistically promoted the infiltration of CD8⁺ and CD4⁺ T cells into tumors (<i>P</i> < 0.05 vs. single inhibitors), thus boosting the antitumor immune responses. In summary, our results revealed that combination immunotherapy with anti-CTLA-4 and anti-PD-1 may present a new, promising regimen to inhibit postoperative breast cancer relapse and lung metastasis and improve patient outcomes, which warrants further investigation in clinical settings.