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Immature monocytic cells within tumors differentiate into immunosuppressive cells in resistant tumors to immunotherapy

ABSTRACT: Immature monocytic cells within tumors differentiate into immunosuppressive cells in resistant tumors to immunotherapy

PROVIDER: PRJNA1272061 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR33827830.fastq.gz	Fastqsanger.gz
	SRR33827831.fastq.gz	Fastqsanger.gz
	SRR33827832.fastq.gz	Fastqsanger.gz
	SRR33827833.fastq.gz	Fastqsanger.gz
	SRR33827834.fastq.gz	Fastqsanger.gz

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Immature monocytic cells within tumors differentiate into immunosuppressive cells in resistant tumors to immunotherapy

Project description:Immune checkpoint inhibitors (ICIs) have improved outcomes in advanced cancers, yet resistance remains a major obsticle. Here, we investigated the role of myeloid cells in shaping the immunosuppressive tumor microenvironment that contributes to ICI resistance. Using mutagenized ICI-sensitive and resistant 4T1 breast cancer clones, we performed single-cell RNA sequencing to characterize immune cell populations post-ICI therapy. We identified monocytic dendritic progenitors (MDPs) and common monocytic progenitors (cMOPs) enriched in sensitive tumors, which may differentiate into immunosuppressive cells in resistant tumors. Analysis of public datasets confirmed the presence of MDP-cMOPs in tumors and blood of breast, lung, and colorectal cancer patients. We found high expression of CXCR4 and IL6R in MDP-cMOPs, and inhibiting these pathways blocked their recruitment and differentiation. Combined targeting of CXCR4 and IL6 pathway with ICI improved responses in resistant tumors, highlighting MDP-cMOPs as contributors to immunotherapy resistance and potential therapeutic targets.

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ILT3 (LILRB4) Promotes the Immunosuppressive Function of Tumor-Educated Human Monocytic Myeloid-Derived Suppressor Cells

Project description:Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that accumulate in the tumor microenvironment (TME). MDSCs have been shown to dampen anti-tumor immune responses and promote tumor growth; however, the mechanisms of MDSC induction and their role in promoting immune suppression in cancer remain poorly understood. Here, we characterized the phenotype and function of monocytic MDSCs (M-MDSCs) generated by co-culture of human peripheral blood mononuclear cells with SK-MEL-5 cancer cells in vitro. We selected the SK-MEL-5 human melanoma cell line to generate M-MDSCs because these cells form subcutaneous tumors rich in myeloid cells in humanized mice. M-MDSCs generated via SK-MEL-5 co-culture expressed low levels of human leukocyte antigen (HLA)-DR, high levels of CD33 and CD11b and suppressed both CD8+ T cell proliferation and IFN-γ secretion. M-MDSCs also expressed higher levels of immunoglobulin-like transcript 3 (ILT3, also known as LILRB4) and immunoglobulin-like transcript 4 (ILT4, also known as LILRB2) on the cell surface compared to monocytes. We, therefore, investigated how ILT3 targeting could modulate M-MDSC cell function. Treatment with an anti-ILT3 antibody impaired the acquisition of the M-MDSC suppressor phenotype and reduced the capacity of M-MDSCs to cause T cell suppression. Finally, in combination with anti-programmed cell death protein 1 (PD1), ILT3 blockade enhanced T cell activation as assessed by IFN-γ secretion. These results suggest that ILT3 expressed on M-MDSCs has a role in inducing immunosuppression in cancer and that antagonism of ILT3 may be useful to reverse the immunosuppressive function of M-MDSCs and enhance the efficacy of immune checkpoint inhibitors.

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