Lei et al. showed that anti-CD3/CD28-stimulated CD4+ T cells induced purified human blood cDC1s and less responsive cDC2s (but not pDCs and moDCs) to express antigen presentation, costimulation, cytokine, and chemokine gene/protein signatures more strongly than PRR signaling. CD4+ T cell-signaled cDC1s were the most potent DCs in an in vitro assay of CTL priming by (tumor) cell-associated antigens, and expressed the clinically favorable DC3 and mregDC signature genes. Genes comprising the mature DC signature were associated with CD8+ and Th1 T cell and cDC1 TME infiltration and response to PD-1 blockade.
Contributed by Paula Hochman
ABSTRACT: Despite their low abundance in the tumor microenvironment (TME), classical type 1 dendritic cells (cDC1) play a pivotal role in anti-cancer immunity, and their abundance positively correlates with patient survival. However, their interaction with CD4(+) T-cells to potentially enable the cytotoxic T lymphocyte (CTL) response has not been elucidated. Here we show that contact with activated CD4(+) T-cells enables human ex vivo cDC1, but no other DC types, to induce a CTL response to cell-associated tumor antigens. Single cell transcriptomics reveals that CD4(+) T-cell help uniquely optimizes cDC1 in many functions that support antigen cross-presentation and T-cell priming, while these changes don't apply to other DC types. We robustly identify "helped" cDC1 in the TME of a multitude of human cancer types by the overlap in their transcriptomic signature with that of recently defined, tumor-infiltrating DC states that prove to be positively prognostic. As predicted from the functional effects of CD4(+) T-cell help, the transcriptomic signature of "helped" cDC1 correlates with tumor infiltration by CTLs and Thelper(h)-1 cells, overall survival and response to PD-1-targeting immunotherapy. These findings reveal a critical role for CD4(+) T-cell help in enabling cDC1 function in the TME and may establish the helped cDC1 transcriptomic signature as diagnostic marker in cancer.
Author Info: (1) Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands. Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. (2) Department
Author Info: (1) Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands. Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. (2) Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands. (3) Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands. Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. (4) Genomics Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (5) Genomics Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (6) Genomics Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands. (7) Aduro Biotech Europe B.V, Oss, The Netherlands. (8) Immune Regulation in Cancer, German Cancer Research Center, Heidelberg, Germany. (9) Laboratory of Cell Stress & Immunity, Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium. (10) Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands. j.g.borst@lumc.nl. Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. j.g.borst@lumc.nl. (11) Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands. y.xiao@lumc.nl. Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands. y.xiao@lumc.nl.
