Inhibition of CSF-1R and IL-6R prevents conversion of cDC2s into immune incompetent tumor-induced DC3s boosting DC-driven therapy potential

Becker, Anouk M.D.; Decker, Annika H.; Flórez-Grau, Georgina; Bakdash, Ghaith; Röring, Rutger J.; Stelloo, Suzan; Vermeulen, Michiel; Piet, Berber; Aarntzen, Erik H.J.G.; Verdoes, Martijn; de Vries, I. Jolanda M.

doi:10.1016/j.xcrm.2023.101386

Cited by 7 publications

(3 citation statements)

References 48 publications

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“…However, as long-term clinical efficacy remains to be seen, there is apparent room for optimization. A proposed mechanism impeding full efficacy for cDC2 vaccines is the presence of soluble factors in the TME such as IL-6 and M-CSF that convert cDC2s to a tolerogenic state upon arrival ( 141 ). One group has taken an antigen-agnostic approach that bypasses both ex vivo culture and need for tumor infiltration by injecting unpulsed cDC2 intratumorally.…”

Section: Vaccines (Adoptive Transfer)mentioning

confidence: 99%

Dendritic cell subsets and implications for cancer immunotherapy

Chen,

Zhang,

Goedegebuure

et al. 2024

Front. Immunol.

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Dendritic cells (DCs) play a central role in the orchestration of effective T cell responses against tumors. However, their functional behavior is context-dependent. DC type, transcriptional program, location, intratumoral factors, and inflammatory milieu all impact DCs with regard to promoting or inhibiting tumor immunity. The following review introduces important facets of DC function, and how subset and phenotype can affect the interplay of DCs with other factors in the tumor microenvironment. It will also discuss how current cancer treatment relies on DC function, and survey the myriad ways with which immune therapy can more directly harness DCs to enact antitumor cytotoxicity.

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Section: Vaccines (Adoptive Transfer)mentioning

confidence: 99%

Dendritic cell subsets and implications for cancer immunotherapy

Chen,

Zhang,

Goedegebuure

et al. 2024

Front. Immunol.

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“…Consistent with shaping immune responses, a recent study demonstrated that CD1c + CD14 + DC3-like cells in humans are related to cDC2s rather than moDCs. Under conditions of tumor-derived IL-6 and M-CSF, cDC2s can be converted into DC3-like cells with protumor activity through the expression of IDO, IL-10, PD-L1, and MERTK [ 96 ]. DC type 3 (DC3) is another subtype previously mentioned in humans that resembles cDC2 [ 35 , 97 ].…”

Section: Dendritic Cells Shape T Cell Response In the Tmementioning

confidence: 99%

Dendritic Cells in Shaping Anti-Tumor T Cell Response

Mazzoccoli,

Liu

2024

Cancers

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Among professional antigen-presenting cells, dendritic cells (DCs) orchestrate innate and adaptive immunity and play a pivotal role in anti-tumor immunity. DCs are a heterogeneous population with varying functions in the tumor microenvironment (TME). Tumor-associated DCs differentiate developmentally and functionally into three main subsets: conventional DCs (cDCs), plasmacytoid DCs (pDCs), and monocyte-derived DCs (MoDCs). There are two major subsets of cDCs in TME, cDC1 and cDC2. cDC1 is critical for cross-presenting tumor antigens to activate cytotoxic CD8+ T cells and is also required for priming earlier CD4+ T cells in certain solid tumors. cDC2 is vital for priming anti-tumor CD4+ T cells in multiple tumor models. pDC is a unique subset of DCs and produces type I IFN through TLR7 and TLR9. Studies have shown that pDCs are related to immunosuppression in the TME through the secretion of immunosuppressive cytokines and by promoting regulatory T cells. MoDCs differentiate separately from monocytes in response to inflammatory cues and infection. Also, MoDCs can cross-prime CD8+ T cells. In this review, we summarize the subsets and functions of DCs. We also discuss the role of different DC subsets in shaping T cell immunity in TME and targeting DCs for potential immunotherapeutic benefits against cancer.

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“…This lack of efficacy in the combination treatment of pexidartinib and durvalumab may be attributed to the broad inhibition profile of pexidartinib [102]. Becker et al discovered that the simultaneous inhibition of CSF1R and IL-6R could prevent cDC2 from transitioning into immunosuppressive tumor-induced DC3, thereby improving the therapeutic potential of DC-driven treatments [103]. CSF1R has demonstrated promise in targeting tumors and the TME.…”

Section: Colony-stimulating Factor 1 Receptor (Csf-1r)mentioning

confidence: 99%

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

Li,

Gong,

Zhou

et al. 2024

IJMS

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Over 120 small-molecule kinase inhibitors (SMKIs) have been approved worldwide for treating various diseases, with nearly 70 FDA approvals specifically for cancer treatment, focusing on targets like the epidermal growth factor receptor (EGFR) family. Kinase-targeted strategies encompass monoclonal antibodies and their derivatives, such as nanobodies and peptides, along with innovative approaches like the use of kinase degraders and protein kinase interaction inhibitors, which have recently demonstrated clinical progress and potential in overcoming resistance. Nevertheless, kinase-targeted strategies encounter significant hurdles, including drug resistance, which greatly impacts the clinical benefits for cancer patients, as well as concerning toxicity when combined with immunotherapy, which restricts the full utilization of current treatment modalities. Despite these challenges, the development of kinase inhibitors remains highly promising. The extensively studied tyrosine kinase family has 70% of its targets in various stages of development, while 30% of the kinase family remains inadequately explored. Computational technologies play a vital role in accelerating the development of novel kinase inhibitors and repurposing existing drugs. Recent FDA-approved SMKIs underscore the importance of blood–brain barrier permeability for long-term patient benefits. This review provides a comprehensive summary of recent FDA-approved SMKIs based on their mechanisms of action and targets. We summarize the latest developments in potential new targets and explore emerging kinase inhibition strategies from a clinical perspective. Lastly, we outline current obstacles and future prospects in kinase inhibition.

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Inhibition of CSF-1R and IL-6R prevents conversion of cDC2s into immune incompetent tumor-induced DC3s boosting DC-driven therapy potential

Cited by 7 publications

References 48 publications

Dendritic cell subsets and implications for cancer immunotherapy

Dendritic cell subsets and implications for cancer immunotherapy

Dendritic Cells in Shaping Anti-Tumor T Cell Response

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

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