Tumors Suppress In Situ Proliferation of Cytotoxic T Cells by Promoting Differentiation of Gr-1+ Conventional Dendritic Cells through IL-6

Mikhailova

et al. 2012

Blood

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IntroductionDendritic cells (DCs) play a central role in initiating and regulating immune responses to foreign and self-antigens. 1 Under steady-state conditions, lymphoid and nonlymphoid tissues contain stable numbers of DCs, which is achieved through a dynamic interplay between the influx of new precursors, DC emigration, and death. Bone marrow (BM)-derived pre-cDCs, the immediate precursor of conventional DCs (cDCs), migrate via blood and enter peripheral lymphoid and nonlymphoid tissues, where they differentiate into cDCs that proliferate for several generations. [2][3][4] Monocytes also participate in the generation of cDCs in some tissues. [5][6][7] Nonlymphoid tissue cDCs emigrate continuously via lymphatics into draining lymph nodes 8 ; similar to the resident populations of lymphoid tissue DCs, most migrant cDCs die in lymphoid tissue and do not reenter the blood circulation. 1 Whether all peripheral tissue cDCs home to lymph nodes or some are destined to die in their local milieu is unclear. Dysregulation or loss-of-function of various cell types and molecules can alter DC homeostasis. 9,10 Chief among them is the cytokine Flt3 ligand, which regulates the number of early progenitors in BM and the rate of DC proliferation in peripheral tissues. 11,12 During acute inflammatory processes, DC numbers fluctuate markedly. Strong inflammatory stimuli can cause an abrupt decrease in the number of lymphoid cDCs, a consequence of maturation-induced apoptosis and migration. 13,14 DC numbers usually rebound within 2 to 3 days, then expand through recruitment of new precursors, augmentation of cDCs proliferation in situ, and differentiation of monocytes into "inflammatory" DCs. 3,[15][16][17][18] Increased expression of granulocyte/macrophage colony stimulating factor (GM-CSF) is considered key to this response. 19 Inflammation also causes egress of tissue DCs into lymph nodes by modulating chemokine receptor expression and altering the structure of regional lymphatics and lymph nodes. [20][21][22] With resolution of inflammation, DC numbers normalize through apoptosis and cytotoxic T-cell mediated killing. 23,24 In chronic inflammatory processes, such as in cancer, DC fate remains poorly understood.The current model of DC ontogeny indicates that the monocyte/ macrophage and DC lineages diverge from a common monocyte-DC progenitor (MDP) in BM. 25 The subsequent defined progenitors in the DC lineage, common DC precursors (CDP or pro-DC) followed by pre-cDCs, are considered irreversibly committed to become terminal DCs. The general assumption of this model is that death completes the life cycle of all DCs. In this study, we report a new termination pathway for cDCs. We found that immunostimulatory CD11c ϩ MHC class II ϩ cDCs retain the capacity to evolve into CD11c Ϫ MHC class II Ϫ macrophage-like cells with potent immunosuppressive activity. We show the critical importance of GM-CSF in maintaining DC identity. By tracking genetically tagged CD11c ϩ cells in vivo, we found that tumors induce a high proportion of cDCs...

Section: Discussionmentioning

confidence: 99%

Immunostimulatory conventional dendritic cells evolve into regulatory macrophage-like cells

Mikhailova

et al. 2012

Blood

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“…Although their studies supported the importance of monocyte-derived DCs, anti-CD11b Abs deplete both DC2 and DC3. We reported that decreasing the frequency of CD11c + DCs in the CD11c-Cre mouse model reduced intratumor CTL proliferation (17); however, this experimental approach depletes all DCs. Thus, the relevance of pre-cDC-derived versus monocytederived tumor DCs to intratumor CTL responses in vivo has yet to be established.…”

mentioning

confidence: 99%

“…Intratumor DCs also promote the expansion and function of tumor-infiltrating CTLs (17,18); however, controversy persists over which DC subpopulation is involved. Several reports have emphasized the dominance of DC1 based on their robust Ag cross-presenting activity (as compared with DC2 and other myeloid populations) and their apparent importance in inhibiting tumor growth in mice treated with adoptive CTL therapy (18)(19)(20).…”

mentioning

confidence: 99%

Tumor Dendritic Cells (DCs) Derived from Precursors of Conventional DCs Are Dispensable for Intratumor CTL Responses

The Journal of Immunology

et al. 2018

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The success of adoptive CTL therapy for cancer depends on interactions between tumor-infiltrating CTLs and cancer cells as well as other cells and molecules in the tumor microenvironment. Tumor dendritic cells (DCs) comprise several subsets: CD103+CD11b− DC1 and CD11b+CD64− DC2, which originate from circulating precursors of conventional DCs, and CD11b+CD64+ DC3, which arise from monocytes. It remains controversial which of these subset(s) promotes intratumor CTL proliferation, expansion, and function. To address this issue, we used the Zbtb46-DTR–transgenic mouse model to selectively deplete DC1 and DC2 from tumors and lymphoid tissues. Wild-type and Zbtb46-DTR bone marrow chimeras were inoculated with B16 melanoma cells that express OVA and were treated with OT-1 CTLs. We found that depletion of DCs derived from precursors of conventional DCs in Zbtb46-DTR bone marrow chimeras abolished CTL proliferation and expansion in tumor-draining lymph nodes. By contrast, intratumor CTL accumulation, proliferation, and IFN-γ expression were unaffected by their absence. We found that adoptive cell therapy increases the frequency of monocyte-derived tumor DC3, which possess the capacity to cross-present tumor Ags and induce CTL proliferation. Our findings support the specialized roles of different DC subsets in the regulation of antitumor CTL responses.

“…Within the tumor microenvironment (TME), some cells differentiated into immunosuppressive DCs and macrophages [6,14] . Cancer has no apparent adverse effect on bone marrow, spleen, or circulating pre-cDC [11] , suggesting that tumor DC dysfunction is initiated by direct exposure to the TME.…”

Section: Research Highlightmentioning

confidence: 99%

“…Recent evidence suggests that effective control of cancer also requires restimulation of CTLs by intra-tumor DCs [4][5][6] . Cancer sabotages this process by impairing the function of DCs and by failing to generate or recruit DC subpopulations that possess superior tumor antigen cross-presentation activity, such as CD103 + DC [7,8] .…”

mentioning

confidence: 99%

The role of TLR2 Activation in Promoting Tumor Dendritic Cell Dysfunction

Cancer Cell Microenviron

Cattral

2016

Dendritic cell (DC) dysfunction in cancer is a well-established phenomenon that is considered one of the main mechanisms of immune evasion. Defects in dendritic cells are caused primarily by tumor-derived factors present in the tumor microenvironment. However, the mechanisms that drive this process remain elusive. In our recent investigations, we reported that tumor-derived versican induces DC dysfunction through TLR2 activation. Ligation of TLR2 by tumor-derived factors sensitizes DCs to IL-6 and IL-10 by increasing their respective cytokine cell surface receptors expression, thus lowering the threshold of STAT3 activation. This mechanism reprograms sensitized DCs into immunosuppressive IL-10 producing cells. Our work revealed key molecular mechanisms of DC dysfunction in cancer and identified TLR2 as a relevant therapeutic target to improve DC immunogenicity and cancer immunotherapy.