Englander Institute for Precision Medicine

BCL2 Inhibition Reveals a Dendritic Cell-Specific Immune Checkpoint That Controls Tumor Immunosurveillance.

TitleBCL2 Inhibition Reveals a Dendritic Cell-Specific Immune Checkpoint That Controls Tumor Immunosurveillance.
Publication TypeJournal Article
Year of Publication2023
AuthorsZhao L, Liu P, Mao M, Zhang S, Bigenwald C, Dutertre C-A, Lehmann CHK, Pan H, Paulhan N, Amon L, Buqué A, Yamazaki T, Galluzzi L, Kloeckner B, Silvin A, Pan Y, Chen H, Tian A-L, Ly P, Dudziak D, Zitvogel L, Kepp O, Kroemer G
JournalCancer Discov
Date Published2023 Nov 01
KeywordsAnimals, Antineoplastic Agents, Dendritic Cells, Humans, Mice, Mice, Knockout, Monitoring, Immunologic, Neoplasms, Programmed Cell Death 1 Receptor, Proto-Oncogene Proteins c-bcl-2

UNLABELLED: We developed a phenotypic screening platform for the functional exploration of dendritic cells (DC). Here, we report a genome-wide CRISPR screen that revealed BCL2 as an endogenous inhibitor of DC function. Knockout of BCL2 enhanced DC antigen presentation and activation as well as the capacity of DCs to control tumors and to synergize with PD-1 blockade. The pharmacologic BCL2 inhibitors venetoclax and navitoclax phenocopied these effects and caused a cDC1-dependent regression of orthotopic lung cancers and fibrosarcomas. Thus, solid tumors failed to respond to BCL2 inhibition in mice constitutively devoid of cDC1, and this was reversed by the infusion of DCs. Moreover, cDC1 depletion reduced the therapeutic efficacy of BCL2 inhibitors alone or in combination with PD-1 blockade and treatment with venetoclax caused cDC1 activation, both in mice and in patients. In conclusion, genetic and pharmacologic BCL2 inhibition unveils a DC-specific immune checkpoint that restrains tumor immunosurveillance.

SIGNIFICANCE: BCL2 inhibition improves the capacity of DCs to stimulate anticancer immunity and restrain cancer growth in an immunocompetent context but not in mice lacking cDC1 or mature T cells. This study indicates that BCL2 blockade can be used to sensitize solid cancers to PD-1/PD-L1-targeting immunotherapy. This article is featured in Selected Articles from This Issue, p. 2293.

Alternate JournalCancer Discov
PubMed ID37623817
PubMed Central IDPMC7615270
Grant List101052444 / ERC_ / European Research Council / International
U54 CA274291 / CA / NCI NIH HHS / United States

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