Augmentation of antitumor function of tumor‐infiltrating lymphocytes against triple‐negative breast cancer by PD‐1 blockade

Abstract

T-cell-based immunotherapy and immune checkpoint blockade have been successfully used to treat several human solid cancers. The present study attempted to investigate the feasibility and efficacy of the antitumor effect of adoptive cell therapy along with programmed cell death protein 1 (PD-1) inhibitor on triplenegative breast cancer (TNBC). Tumor infiltration lymphocytes (TILs) from TNBC mouse tumor tissues were isolated and expanded, and TILs for adoptive cell therapy (TILs-ACT) were applied in combination with a PD-1 inhibitor to the TNBC mouse model. The pre-and post-therapy antitumor efficacy, cytokine secretion, and pathological changes were assessed both in vitro and in vivo. We found that TILs exhibited higher IFN-γ and TNF-α secretion than conventional T cells. The TILs-ACT combined with PD-1 inhibitor promoted active T-cell infiltration into the tumor tissue and exerted a strong antitumor effect in an in vivo model. Additionally, the strategy could downregulate the expression of inhibitory marker PD-1 on TILs. In conclusion, PD-1 blockade regulated T-cell exhaustion that synergized with adoptive TIL transfer immunotherapy, leading to eradication of established TNBC tumors. These findings might be useful in developing a feasible and effective therapeutic approach for TNBC.

Clinicopathologic Features and Immune Cell Subtypes Analysis of Tumor-infiltrating Lymphocytes Rich Invasive Breast Carcinoma of No Special Type

“…Exhausted T cells are a group of dysfunctional T cells, which are present in chronic infections or tumors. The most significant characteristics of exhausted T cells are attenuated effector cytotoxicity, reduced cytokine production, and upregulation of multiple inhibitory molecular receptors (eg, PD-1, TIM-3, and LAG-3) 28 . It is clear that tumor-infiltrating lymphocytes are the most important group of immune cells in the TME and are a direct force to suppress or eliminate tumor cells.…”

“…The most significant characteristics of exhausted T cells are attenuated effector cytotoxicity, reduced cytokine production, and upregulation of multiple inhibitory molecular receptors (eg, PD-1, TIM-3, and LAG-3). 28 It is clear that tumor-infiltrating lymphocytes are the most important group of immune cells in the TME and are a direct force to suppress or eliminate tumor cells. However, even these special cells, which are supposed to be an important immune monitoring and clearance force, can be gradually weakened or exhausted to varying degrees in the TME.…”

Emerging Trends in Immunotherapy for Cancer

“…This study provided evidence that TILs therapy is effective in treating epithelial cancers, which were previously thought to be a limitation of cell-based therapy. In addition, TILs in combination with anti-PD-1 have shown promising anti-tumor responses in multiple cancer types, notably PDL1 negative metastatic cervical cancer [ 141 ], metastatic osteosarcoma [ 147 ], triple-negative breast cancer [ 148 ].…”