Abstract
Although the milestone discovery of immune checkpoint blockade (ICB) has been translated into clinical practice, only a fraction of patients can benefit from it with durable responses and subsequent long-term survival. Here, we tested the anti-tumor effect of combining PD-L1 blockade with 4-1BB costimulation in 3LL and 4T1.2 murine tumor models. Dual treatment induced further tumor regression and enhanced survival in tumor-bearing mice more so than PD-L1 and 4-1BB mAb alone. It was demonstrated that dual anti-PD-L1/anti-4-1BB immunotherapy increased the number of intratumoral CD103+CD8+ T cells and altered their distribution. Phenotypically, CD103+CD8+ T cells expressed a 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. In a human setting, more CD8+ T cells differentiated into CD103+CD8+ T cells in the peripheral tumor region of lung cancer tissues than in 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.
Highlights
PD-1/PD-L1 blockade immunotherapy has shown potential for many types of cancer, but its clinic efficacy is limited, partly due to the absence of tumoral effector cytotoxic T lymphocytes (CTLs) infiltration [1, 2]
Anti-4-1BB and Anti-PD-L1 Abs Have a Synergistic Anti-tumor Activity. To investigate whether it could improve the therapeutic efficacy of immune checkpoint blockade (ICB) in the setting of established tumors, we co-administered anti-PD-L1 mAb and anti-4-1BB mAb to tumor-bearing mice
All mice received twice-weekly injection of rat IgG isotype control, anti-PD-L1 mAb, anti-4-1BB mAb, or anti-PDL1 mAb combined with anti-4-1BB mAb, respectively, beginning at day 10 after tumor inoculation
Summary
PD-1/PD-L1 blockade immunotherapy has shown potential for many types of cancer, but its clinic efficacy is limited, partly due to the absence of tumoral effector cytotoxic T lymphocytes (CTLs) infiltration [1, 2]. Recent evidence showed that a subset of CD8+T cells became resident within tissue environments [8, 9] These tissue-resident T cells were distinct from their circulating counterparts, and have been involved in protective immune responses against foreign pathogens [10, 11]. In a tumor setting, emerging evidence reported that there were resident T cells within the tumor microenvironment [12,13,14,15]. These resident cells could have a prognostic value in human cancers [16,17,18]. The exact function of resident T cells in anti-tumor immune response and whether they respond to ICB immunotherapy are still unknown
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