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Targeting tumour-reprogrammed myeloid cells: the new battleground in cancer immunotherapy.

ABSTRACT: Tumour microenvironment is a complex ecosystem in which myeloid cells are the most abundant immune elements. This cell compartment is composed by different cell types, including neutrophils, macrophages, dendritic cells, and monocytes but also unexpected cell populations with immunosuppressive and pro-tumour roles. Indeed, the release of tumour-derived factors influences physiological haematopoiesis producing unconventional cells with immunosuppressive and tolerogenic functions such as myeloid-derived suppressor cells. These pro-tumour myeloid cell populations not only support immune escape directly but also assist tumour invasion trough non-immunological activities. It is therefore not surprising that these cell subsets considerably impact in tumour progression and cancer therapy resistance, including immunotherapy, and are being investigated as potential targets for developing a new era of cancer therapy. In this review, we discuss emerging strategies able to modulate the functional activity of these tumour-supporting myeloid cells subverting their accumulation, recruitment, survival, and functions. These innovative approaches will help develop innovative, or improve existing, cancer treatments.

SUBMITTER: De Sanctis F

PROVIDER: S-EPMC9513014 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Targeting tumour-reprogrammed myeloid cells: the new battleground in cancer immunotherapy.

De Sanctis Francesco F Adamo Annalisa A Canè Stefania S Ugel Stefano S

Seminars in immunopathology 20220926 2

Tumour microenvironment is a complex ecosystem in which myeloid cells are the most abundant immune elements. This cell compartment is composed by different cell types, including neutrophils, macrophages, dendritic cells, and monocytes but also unexpected cell populations with immunosuppressive and pro-tumour roles. Indeed, the release of tumour-derived factors influences physiological haematopoiesis producing unconventional cells with immunosuppressive and tolerogenic functions such as myeloid-d ...[more]

PMID: 36161514

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Project description:Immune checkpoint inhibitors targeting programmed cell death protein 1, programmed death-ligand 1, and cytotoxic T-lymphocyte-associated protein 4 provide deep and durable treatment responses which have revolutionized oncology. However, despite over 40% of cancer patients being eligible to receive immunotherapy, only 12% of patients gain benefit. A key to understanding what differentiates treatment response from non-response is better defining the role of the innate immune system in anti-tumor immunity and immune tolerance. Teleologically, myeloid cells, including macrophages, dendritic cells, monocytes, and neutrophils, initiate a response to invading pathogens and tissue repair after pathogen clearance is successfully accomplished. However, in the tumor microenvironment (TME), these innate cells are hijacked by the tumor cells and are imprinted to furthering tumor propagation and dissemination. Major advancements have been made in the field, especially related to the heterogeneity of myeloid cells and their function in the TME at the single cell level, a topic that has been highlighted by several recent international meetings including the 2021 China Cancer Immunotherapy workshop in Beijing. Here, we provide an up-to-date summary of the mechanisms by which major myeloid cells in the TME facilitate immunosuppression, enable tumor growth, foster tumor plasticity, and confer therapeutic resistance. We discuss ongoing strategies targeting the myeloid compartment in the preclinical and clinical settings which include: (1) altering myeloid cell composition within the TME; (2) functional blockade of immune-suppressive myeloid cells; (3) reprogramming myeloid cells to acquire pro-inflammatory properties; (4) modulating myeloid cells via cytokines; (5) myeloid cell therapies; and (6) emerging targets such as Siglec-15, TREM2, MARCO, LILRB2, and CLEVER-1. There is a significant promise that myeloid cell-based immunotherapy will help advance immuno-oncology in years to come.

Project description:BackgroundImmunotherapy has emerged as a crucial treatment modality for solid tumours, yet tumours often evade immune surveillance. There is an imperative to uncover novel immune regulators that can boost tumour immunogenicity and increase the efficacy of immune checkpoint blockade (ICB) therapy. Epigenetic regulators play critical roles in tumour microenvironment remodelling, and N6-methyladenosine (m6A) is known to be involved in tumourigenesis. However, the role of m6A in regulating T-cell function and enhancing anti-tumour immunity remains unexplored.MethodsSeveral cancer cell lines were treated with STM2457, an enzymatic inhibitor of RNA m6A methyltransferase METTL3, and explored the transcriptome changes with RNA sequencing (RNA-seq). We then utilised mouse melanoma (B16) and mouse colorectal adenocarcinoma (MC38) models to investigate the effects of METTL3 inhibition on immunotherapy, and analysed the dynamics of the tumour microenvironment via single-cell RNA-seq (scRNA-seq). Furthermore, in vitro and in vivo T-cell cytotoxicity killing assay and CRISPR Cas9-mediated m6A reader YTHDF1-3 knockout in B16 were performed to assess the role and the molecular mechanism of RNA m6A in tumour killing. Finally, the efficacy of METTL3 inhibition was also tested on human melanoma model (A375) and human T cells.ResultsWe demonstrate that inhibiting METTL3 augments tumour immunogenicity and sustains T-cell function, thereby enhancing responsiveness to ICB therapy. Mechanistically, METTL3 inhibition triggers an interferon response within tumour cells, amplifying the anti-tumour immune response, along with deletion of the m6A reader protein YTHDF2 in tumours inhibiting major histocompatibility complex (MHC)-I degradation. Remarkably, these anti-tumour effects are reliant on the immune system. Specifically, METTL3 inhibition enhances interferon-gamma (IFNγ) and granzyme B (GzmB) expression, thereby strengthening T-cell killing ability, and concurrently dampening the expression of exhaustion-related genes.ConclusionTargeting METTL3 enhances anti-tumour immunity by boosting T-cell cytotoxicity and reversing T-cell exhaustion. Our study positions METTL3 as an epigenetic checkpoint, highlighting the potential of targeting METTL3 to invigorate intrinsic anti-tumour defenses and overcome immune resistance.Key pointsTargeting METTL3 augments tumour cell immunogenicity and sustains T-cell function. T cell with METTL3 inhibition can reverse T-cell exhaustion, and promote expression of IFNγ and GzmB, thereby enhancing cytotoxicity in anti-PD-1 therapy. YTHDF2 deletion in tumours prolong the lifespan of MHC-I mRNAs.

Dataset Information

Targeting tumour-reprogrammed myeloid cells: the new battleground in cancer immunotherapy.

Publications

Targeting tumour-reprogrammed myeloid cells: the new battleground in cancer immunotherapy.

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