AUTHOR=Wang Yichen , Zhang Xuyao , Xu Caili , Nan Yanyang , Fan Jiajun , Zeng Xian , Kwon Byoung S. , Ju Dianwen 

TITLE=Targeting 4-1BB and PD-L1 induces potent and durable antitumor immunity in B-cell lymphoma

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1004475

DOI=10.3389/fimmu.2022.1004475

ISSN=1664-3224

ABSTRACT=Although monoclonal antibodies targeting PD-1/PD-L1 demonstrate clinical benefits in certain cancer types, low response rate and resistance remain the main challenges for the application of these immune checkpoint inhibitors (ICIs). As a costimulatory molecule, 4-1BB could enhance T cell proliferation and activation. Herein, the synergetic antitumor effect and underlying mechanism of 4-1BB agonist combined with PD-1/PD-L1 blockade were determined in B-cell lymphoma (BCL). Our results showed that combining anti-PD-L1 ICI and 4-1BB agonist elicited regression of BCL and significantly extended the survival compared to either monotherapy. Co-targeting PD-L1 and 4-1BB preferentially promoted intratumoral cytotoxic lymphocytes infiltration and remodeled their function. RNA-sequence analysis uncovered a series of up-regulated genes related to the activation and proliferation of cytotoxic T lymphocytes, which were further characterized by various increased cytokines including IFN-γ, granzyme B and perforin. Furthermore, depleting CD8+ T cells not CD4+ T cells totally abrogated the antitumor efficacy, indicating the crucial function of CD8+ T cell subset in the combination therapy. In summary, our findings demonstrated that 4-1BB agonistic antibody intensified the antitumor immunity of anti-PD-1/PD-L1 ICI via promoting CD8+ T cell infiltration and activation, providing a novel therapeutic strategy to BCL.