Turning enemies into allies—reprogramming tumor-associated macrophages for cancer therapy

Molgora, Martina; Colonna, Marco

doi:10.1016/j.medj.2021.05.001

Cited by 26 publications

(20 citation statements)

References 134 publications

(174 reference statements)

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“…As detailed above, TREM2 is known to recognize a wide range of ligands, but it remains unknown which specific ligands it recognizes in the TME [48]. Nevertheless, these recent studies indicate that antagonistic anti-TREM2 mAbs have the potential to augment antitumor T cells responses, although the impact of blockade in the context of direct targeting mAb immunotherapy and ADCP warrants further investigation.…”

Section: Triggering-receptor-expressed On Myeloid Cells 2 (Trem2)mentioning

confidence: 99%

“…Concurrent work in murine tumor models by Molgora et al [ 191 ] demonstrated that treatment with anti-TREM2 mAb suppressed tumor growth, augmented antitumor effector T cell responses and reduced MRC1 + CX 3 CR1 + macrophages in the tumor infiltrate when combined with anti-PD-1 mAb therapy [ 191 ]. As detailed above, TREM2 is known to recognize a wide range of ligands, but it remains unknown which specific ligands it recognizes in the TME [ 48 ]. Nevertheless, these recent studies indicate that antagonistic anti-TREM2 mAbs have the potential to augment antitumor T cells responses, although the impact of blockade in the context of direct targeting mAb immunotherapy and ADCP warrants further investigation.…”

Section: Tam Repolarizationmentioning

confidence: 99%

“… TAM-associated markers. Expression of genes in TAMs that phenotypically and functionally associate with protumor (blue) and antitumor (red) outcomes in the context of tumor progression and/or efficacy of direct targeting mAb therapy (adapted from [ 48 ]). …”

Section: Figurementioning

confidence: 99%

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Remodeling the Tumor Myeloid Landscape to Enhance Antitumor Antibody Immunotherapies

Hussain

Cragg

Beers

2021

Cancers

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Among the diverse tumor resident immune cell types, tumor-associated macrophages (TAMs) are often the most abundant, possess an anti-inflammatory phenotype, orchestrate tumor immune evasion and are frequently associated with poor prognosis. However, TAMs can also be harnessed to destroy antibody-opsonized tumor cells through the process of antibody-dependent cellular phagocytosis (ADCP). Clinically important tumor-targeting monoclonal antibodies (mAb) such as Rituximab, Herceptin and Cetuximab, function, at least in part, by inducing macrophages to eliminate tumor cells via ADCP. For IgG mAb, this is mediated by antibody-binding activating Fc gamma receptors (FcγR), with resultant phagocytic activity impacted by the level of co-engagement with the single inhibitory FcγRIIb. Approaches to enhance ADCP in the tumor microenvironment include the repolarization of TAMs to proinflammatory phenotypes or the direct augmentation of ADCP by targeting so-called ‘phagocytosis checkpoints’. Here we review the most promising new strategies targeting the cell surface molecules present on TAMs, which include the inhibition of ‘don’t eat me signals’ or targeting immunostimulatory pathways with agonistic mAb and small molecules to augment tumor-targeting mAb immunotherapies and overcome therapeutic resistance.

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Section: Triggering-receptor-expressed On Myeloid Cells 2 (Trem2)mentioning

confidence: 99%

Section: Tam Repolarizationmentioning

confidence: 99%

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Remodeling the Tumor Myeloid Landscape to Enhance Antitumor Antibody Immunotherapies

Hussain

Cragg

Beers

2021

Cancers

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“…Recently, attention has been focused on TREM2-expressing tumor-associated macrophages (TAMs). TAMs represent a major component of the tumor microenvironment (TME), being primarily immunosuppressive and associated with poor prognosis [11][12][13]. TAMs can affect tumor growth, directly and indirectly, promoting tumor cell survival and proliferation, as well as angiogenesis, invasiveness, and immune evasion.…”

Section: Introductionmentioning

confidence: 99%

Exploring the Impact of TREM2 in Tumor-Associated Macrophages

2022

Self Cite

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Tumor-associated macrophages (TAMs) represent a key component of the tumor microenvironment and are generally associated with immunosuppression and poor prognosis. TREM2 is a transmembrane receptor of the immunoglobulin superfamily expressed in myeloid cells. TREM2 has been extensively studied in microglia and neurodegenerative diseases and recently emerged as a marker of pro-tumorigenic macrophages. The accumulation of TREM2-expressing TAMs was reported across numerous cancer patients and tumor models. TREM2 genetic blockade or TREM2 targeting with antibodies resulted in improved tumor control, enhanced response to anti-PD1, and significant changes in the tumor immune landscape. Preclinical studies paved the way for an ongoing clinical trial with a TREM2 depleting antibody and inspired further exploration of TREM2 targeting therapies. Here, we review the current knowledge about the impact of TREM2 in cancer, with an emphasis on the TREM2+ macrophage signature across different cancer types, the contribution of TREM2 to TAM phenotype and function, and the promising effects of TREM2 modulation.

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“…The presence and accumulation of pro-tumorigenic TIMs correlates with resistance to various cancer treatments (including immunotherapy) and poor patient outcomes (Sharma et al, 2017). Thus, reprogramming TIMs towards an anti-tumorigenic phenotype is an attractive strategy for cancer therapy that has shown efficacy across therapeutic modalities and tumor types in both preclinical and clinical studies (Kowal et al, 2019;Molgora and Colonna, 2021).…”

Section: Introductionmentioning

confidence: 99%

Targeting Metabolic Pathways of Myeloid Cells Improves Cancer Immunotherapy

Li¹,

Bolyard²,

Xu³

et al. 2021

Front. Cell Dev. Biol.

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Tumor-infiltrating myeloid cells are a prominent pro-tumorigenic immune cell population that limit host anti-tumor immunity and present a significant obstacle for many cancer immunotherapies. Targeting the mechanisms regulating myeloid cell function within the tumor microenvironment may overcome immunotherapy resistance in some cancers. Recent discoveries in the emerging field of immunometabolism reveal that the metabolic profiles of intratumoral myeloid cells are rewired to adapt to the nutrition-limited tumor microenvironment, and this shapes their pro-tumor phenotypes. Interestingly, metabolic modulation can shift these myeloid cells toward the immune-stimulating anti-tumor phenotype. In this review, we will highlight the roles of specific metabolic pathways in the activation and function of myeloid cells, and discuss the therapeutic value of metabolically reprogramming myeloid cells to augment and improve outcomes with cancer immunotherapy.

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Turning enemies into allies—reprogramming tumor-associated macrophages for cancer therapy

Cited by 26 publications

References 134 publications

Remodeling the Tumor Myeloid Landscape to Enhance Antitumor Antibody Immunotherapies

Remodeling the Tumor Myeloid Landscape to Enhance Antitumor Antibody Immunotherapies

Exploring the Impact of TREM2 in Tumor-Associated Macrophages

Targeting Metabolic Pathways of Myeloid Cells Improves Cancer Immunotherapy

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