4-1BB Agonism Combined With PD-L1 Blockade Increases the Number of Tissue-Resident CD8+ T Cells and Facilitates Tumor Abrogation

Abstract

Although the milestone discovery of immune checkpoint blockade (ICB) has been translated into clinical success, only a fraction of patients can benefit from it with durable responses and long-term survival. Here, we tested the effect of combining PD-L1 blockade with4-1BB costimulation in 3LL and 4T1.2 murine tumor model. Dual treatment induced further tumor regression and enhanced survival in tumor-bearing mice, than PD-L1 and 4-1BB mAb alone. It was demonstrated that dual anti-PD-L1/anti-4-1BB immunotherapy increased number and altered distribution of intratumoral CD103+CD8+ T cells. Phenotypically, CD103+CD8+ T cells expressed higher level of 4-1BB and PD-1 than their CD103- counterparts. Administration of PD-L1 mAb and 4-1BB mAb further increased the cytolytic capacity of CD103+CD8+ T cells. In vivo, CD103-CD8+ T cells could differentiate into CD103+CD8+ progeny cells. More CD8+ T cells differentiated into CD103+CD8+ T cell in peripheral tumor region of human lung cancer tissues rather than the central tumor region. Collectively, infiltrated CD103+CD8+ T cells served as a potential effector T cell population. Combining 4-1BB agonism with PD-L1 blockade could increase tumor infiltrated CD103+CD8+T cells, thereby facilitating tumor regression.