CD4(+) T cells can "help" or "license" conventional type 1 dendritic cells (cDC1s) to induce CD8(+) cytotoxic T lymphocyte (CTL) anticancer responses, as proven in mouse models. We recently... Show moreCD4(+) T cells can "help" or "license" conventional type 1 dendritic cells (cDC1s) to induce CD8(+) cytotoxic T lymphocyte (CTL) anticancer responses, as proven in mouse models. We recently identified cDC1s with a transcriptomic imprint of CD4(+) T-cell help, specifically in T-cell-infiltrated human cancers, and these cells were associated with a good prognosis and response to PD-1-targeting immunotherapy. Here, we delineate the mechanism of cDC1 licensing by CD4(+) T cells in humans. Activated CD4(+) T cells produce IFN beta via the STING pathway, which promotes MHC-I antigen (cross-)presentation by cDC1s and thereby improves their ability to induce CTL anticancer responses. In cooperation with CD40 ligand (L), IFN beta also optimizes the costimulatory and other functions of cDC1s required for CTL response induction. IFN-I-producing CD4(+) T cells are present in diverse T-cell-infiltrated cancers and likely deliver "help" signals to CTLs locally, according to their transcriptomic profile and colocalization with "helped/licensed" cDCs and tumor-reactive CD8(+) T cells. In agreement with this scenario, the presence of IFN-I-producing CD4(+) T cells in the TME is associated with overall survival and the response to PD-1 checkpoint blockade in cancer patients. Show less
Miao, B.P.; Hu, Z.Q.; Mezzadra, R.; Hoeijmakers, L.; Fauster, A.; S.C. du; ... ; Sun, C. 2023
The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current ca...Show moreThe dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1−PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses. Show less
Lei, X.; Khatri, I.; Wit, T. de; Rink, I. de; Nieuwland, M.; Kerkhoven, R.; ... ; Xiao, Y.L. 2023
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... Show moreDespite 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.The presence of classical type 1 dendritic cells (cDC1) positively influences prognosis in cancer, but their intricate networking with the various T cell types found in the tumour microenvironment is not fully appreciated. Here the authors show that cDC1 encounter with CD4(+) helper T-cells transforms their gene expression signature, and these "helped" dendritic cells enable the function of anti-tumour cytotoxic T-cells. Show less
Lei, X.; Palomero, J.; Rink, I. de; Wit, T. de; Baalen, M. van; Xiao, Y.L.; Borst, J. 2021
Toll-like receptor 5 (TLR5) is the receptor of bacterial Flagellin. Reportedly, TLR5 engagement helps to combat infections, especially at mucosal sites, by evoking responses from epithelial cells... Show moreToll-like receptor 5 (TLR5) is the receptor of bacterial Flagellin. Reportedly, TLR5 engagement helps to combat infections, especially at mucosal sites, by evoking responses from epithelial cells and immune cells. Here we report that TLR5 is expressed on a previously defined bipotent progenitor of macrophages (M phi s) and osteoclasts (OCs) that resides in the mouse bone marrow (BM) and circulates at low frequency in the blood. In vitro, Flagellin promoted the generation of M phi s, but not OCs from this progenitor. In vivo, M phi/OC progenitors were recruited from the blood into the lung upon intranasal inoculation of Flagellin, where they rapidly differentiated into M phi s. Recruitment of the M phi/OC progenitors into the lung was likely promoted by the CCL2/CCR2 axis, since the progenitors expressed CCR2 and type 2 alveolar epithelial cells (AECs) produced CCL2 upon stimulation by Flagellin. Moreover, CCR2 blockade reduced migration of the M phi/OC progenitors toward lung lavage fluid (LLF) from Flagellin-inoculated mice. Our study points to a novel role of the Flagellin/TLR5 axis in recruiting circulating M phi/OC progenitors into infected tissue and stimulating these progenitors to locally differentiate into M phi s. The progenitor pathway to produce M phi s may act, next to monocyte recruitment, to fortify host protection against bacterial infection at mucosal sites. Show less
Xiao, Y.L.; Halteren, A.G.S. van; Lei, X.; Borst, J.; Steenwijk, E.; Wit, T. de; ... ; Bos, C. van den 2020
Langerhans cell histiocytosis (LCH) is a myeloid neoplasia, driven by sporadic activating mutations in the MAPK pathway. The misguided myeloid dendritic cell (DC) model proposes that high-risk,... Show moreLangerhans cell histiocytosis (LCH) is a myeloid neoplasia, driven by sporadic activating mutations in the MAPK pathway. The misguided myeloid dendritic cell (DC) model proposes that high-risk, multisystem, risk-organ-positive (MS-RO+) LCH results from driver mutation in a bone marrow (BM)-resident multipotent hematopoietic progenitor, while low-risk, MS-RO- and single-system LCH would result from driver mutation in a circulating or tissue-resident, DC-committed precursor. We have examined the CD34(+)c-Kit(+)Flt3(+) myeloid progenitor population as potential mutation carrier in all LCH disease manifestations. This population contains oligopotent progenitors of monocytes (Mo's)/macrophages (M Phi s), osteoclasts (OCs), and DCs. CD34(+)c-Kit(+)Flt3(+) cells from BM of MS-RO+ LCH patients produced Langerhans cell (LC)-like cells in vitro. Both LC-like and DC offspring from this progenitor carried the BRAF mutation, confirming their common origin. In both high- and low-risk LCH patients, CD34(+)c-Kit(+)Flt3(+) progenitor frequency in blood was higher than in healthy donors. In one MS-RO+ LCH patient, CD34(+)c-Kit(+)Flt3(+) cell frequency in blood and its BRAF-mutated offspring reported response to chemotherapy. CD34(+)c-Kit(+)Flt3(+) progenitors from blood of both high- and low-risk LCH patients gave rise to DCs and LC-like cells in vitro, but the driver mutation was not easily detectable, likely due to low frequency of mutated progenitors. Mutant BRAF alleles were found in Mo's/M Phi s, DCs, LC-like cells, and/or OC-like cells in lesions and/or Mo and DCs in blood of multiple low-risk patients. We therefore hypothesize that in both high- and low-risk LCH, the driver mutation is present in a BM-resident myeloid progenitor that can be mobilized to the blood. Show less
