Tumor-Associated Macrophage Status in Cancer Treatment

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Abstract

Tumor-associated macrophages (TAMs) represent the most abundant innate immune cells in tumors. TAMs, exhibiting anti-inflammatory phenotype, are key players in cancer progression, metastasis and resistance to therapy. A high TAM infiltration is generally associated with poor prognosis, but macrophages are highly plastic cells that can adopt either proinflammatory/antitumor or anti-inflammatory/protumor features in response to tumor microenvironment stimuli. In the context of cancer therapy, many anticancer therapeutics, apart from their direct effect on tumor cells, display different effects on TAM activation status and density. In this review, we aim to evaluate the indirect effects of anticancer therapies in the modulation of TAM phenotypes and pro/antitumor activity.

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Macrophage regulation of tumor responses to anticancer therapies.

Michele De Palma, Claire Lewis (2013)

Tumor-associated macrophages (TAMs) promote key processes in tumor progression, like angiogenesis, immunosuppression, invasion, and metastasis. Increasing studies have also shown that TAMs can either enhance or antagonize the antitumor efficacy of cytotoxic chemotherapy, cancer-cell targeting antibodies, and immunotherapeutic agents--depending on the type of treatment and tumor model. TAMs also drive reparative mechanisms in tumors after radiotherapy or treatment with vascular-targeting agents. Here, we discuss the biological significance and clinical implications of these findings, with an emphasis on novel approaches that effectively target TAMs to increase the efficacy of such therapies. Copyright © 2013 Elsevier Inc. All rights reserved.

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Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.

Francois Ghiringhelli, Cédric Ménard, Pierre Emmanuel Puig … (2007)

CD4+CD25+ regulatory T cells are involved in the prevention of autoimmune diseases and in tumor-induced tolerance. We previously demonstrated in tumor-bearing rodents that one injection of cyclophosphamide could significantly decrease both numbers and suppressive functions of regulatory T cells, facilitating vaccine-induced tumor rejection. In humans, iterative low dosing of cyclophosphamide, referred to as "metronomic" therapy, has recently been used in patients with advanced chemotherapy resistant cancers with the aim of reducing tumor angiogenesis. Here we show that oral administration of metronomic cyclophosphamide in advanced cancer patients induces a profound and selective reduction of circulating regulatory T cells, associated with a suppression of their inhibitory functions on conventional T cells and NK cells leading to a restoration of peripheral T cell proliferation and innate killing activities. Therefore, metronomic regimen of cyclophosphamide does not only affect tumor angiogenesis but also strongly curtails immunosuppressive regulatory T cells, favoring a better control of tumor progression. Altogether these data support cyclophosphamide regimen as a valuable treatment for reducing tumor-induced immune tolerance before setting to work anticancer immunotherapy.

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In vivo imaging reveals a tumor-associated macrophage–mediated resistance pathway in anti–PD-1 therapy

Sean Arlauckas, Christopher S. Garris, Rainer H. Kohler … (2017)

Monoclonal antibodies (mAbs) targeting the immune checkpoint anti–programmed cell death protein 1 (aPD-1) have demonstrated impressive benefits for the treatment of some cancers; however, these drugs are not always effective, and we still have a limited understanding of the mechanisms that contribute to their efficacy or lack thereof. We used in vivo imaging to uncover the fate and activity of aPD-1 mAbs in real time and at subcellular resolution in mice. We show that aPD-1 mAbs effectively bind PD-1+ tumor-infiltrating CD8+ T cells at early time points after administration. However, this engagement is transient, and aPD-1 mAbs are captured within minutes from the T cell surface by PD-1– tumor-associated macrophages. We further show that macrophage accrual of aPD-1 mAbs depends both on the drug’s Fc domain glycan and on Fc receptors (FcRs) expressed by host myeloid cells and extend these findings to the human setting. Finally, we demonstrate that in vivo blockade of FcRs before aPD-1 mAb administration substantially prolongs aPD-1 mAb binding to tumor-infiltrating CD8+ T cells and enhances immunotherapy-induced tumor regression in mice. These investigations yield insight into aPD-1 target engagement in vivo and identify specific Fc/FcR interactions that can be modulated to improve checkpoint blockade therapy.

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Author and article information

Journal

Journal ID (nlm-ta): Cancers (Basel)

Journal ID (iso-abbrev): Cancers (Basel)

Journal ID (publisher-id): cancers

Title: Cancers

Publisher: MDPI

ISSN (Electronic): 2072-6694

Publication date (Electronic): 21 July 2020

Publication date Collection: July 2020

Volume: 12

Issue: 7

Electronic Location Identifier: 1987

Affiliations

[1 ]Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; fabiananapolitano@ 123456libero.it (F.N.); sarah_ds@ 123456hotmail.it (S.D.S.)

[2 ]Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvador Allende, Baronissi, 84081 Salerno, Italy; spisanti@ 123456unisa.it (S.P.); rmartinelli@ 123456unisa.it (R.M.)

Author notes

[* ]Correspondence: annamaria.malfitano@ 123456unina.it (A.M.M.); portella@ 123456unina.it (G.P.); Tel.: +39-081-746-3056 (G.P.)

Author information

Anna Maria Malfitano https://orcid.org/0000-0002-6193-2835

Rosanna Martinelli https://orcid.org/0000-0002-6524-6752

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Publisher ID: cancers-12-01987

DOI: 10.3390/cancers12071987

PMC ID: 7409350

PubMed ID: 32708142

SO-VID: 251eadb8-9a64-479e-9b72-319105a54573

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Tumor-Associated Macrophage Status in Cancer Treatment

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Karger: Oncology

Most cited references 84

Macrophage regulation of tumor responses to anticancer therapies.

Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.

In vivo imaging reveals a tumor-associated macrophage–mediated resistance pathway in anti–PD-1 therapy

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