Targeting tumor-associated macrophages to synergize tumor immunotherapy

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Abstract

The current treatment strategies in advanced malignancies remain limited. Notably, immunotherapies have raised hope for a successful control of these advanced diseases, but their therapeutic responses are suboptimal and vary considerably among individuals. Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and are often correlated with poor prognosis and therapy resistance, including immunotherapies. Thus, a deeper understanding of the complex roles of TAMs in immunotherapy regulation could provide new insight into the TME. Furthermore, targeting of TAMs is an emerging field of interest due to the hope that these strategies will synergize with current immunotherapies. In this review, we summarize recent studies investigating the involvement of TAMs in immune checkpoint inhibition, tumor vaccines and adoptive cell transfer therapies, and discuss the therapeutic potential of targeting TAMs as an adjuvant therapy in tumor immunotherapies.

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Most cited references 170

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The Immune Landscape of Cancer

Fadlo Khuri, Natália Aredes, Jung Lee … (2018)

We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.

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Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

F. Stephen Hodi, Steven J O'Day, David F McDermott … (2010)

An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

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Oncology meets immunology: the cancer-immunity cycle.

Daniel S. Chen, Ira Mellman (2013)

The genetic and cellular alterations that define cancer provide the immune system with the means to generate T cell responses that recognize and eradicate cancer cells. However, elimination of cancer by T cells is only one step in the Cancer-Immunity Cycle, which manages the delicate balance between the recognition of nonself and the prevention of autoimmunity. Identification of cancer cell T cell inhibitory signals, including PD-L1, has prompted the development of a new class of cancer immunotherapy that specifically hinders immune effector inhibition, reinvigorating and potentially expanding preexisting anticancer immune responses. The presence of suppressive factors in the tumor microenvironment may explain the limited activity observed with previous immune-based therapies and why these therapies may be more effective in combination with agents that target other steps of the cycle. Emerging clinical data suggest that cancer immunotherapy is likely to become a key part of the clinical management of cancer. Copyright © 2013 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Xiao Xu: zjxu@zju.edu.cn

Journal

Journal ID (nlm-ta): Signal Transduct Target Ther

Journal ID (iso-abbrev): Signal Transduct Target Ther

Title: Signal Transduction and Targeted Therapy

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 2095-9907

ISSN (Electronic): 2059-3635

Publication date (Electronic): 23 February 2021

Publication date PMC-release: 23 February 2021

Publication date Collection: 2021

Volume: 6

Electronic Location Identifier: 75

Affiliations

[1 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People’s Hospital, , Zhejiang University School of Medicine, ; Hangzhou, China

[2 ]GRID grid.506261.6, ISNI 0000 0001 0706 7839, NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, ; Hangzhou, China

[3 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, , Zhejiang University School of Medicine, ; Hangzhou, China

Article

Publisher ID: 484

DOI: 10.1038/s41392-021-00484-9

PMC ID: 7900181

PubMed ID: 33619259

SO-VID: 0e3130dc-6600-40ad-891f-9f916e8ec297

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 20 March 2020

Date revision received : 30 July 2020

Date accepted : 15 October 2020

Funding

Funded by: FundRef https://doi.org/10.13039/501100010909, National Science Foundation of China | Young Scientists Fund;

Award ID: 81625003

Award Recipient : Xiao Xu

Funded by: FundRef https://doi.org/10.13039/501100010905, National Science Foundation of China | Major Research Plan;

Award ID: 2017ZX10203205

Award ID: 81930016

Award ID: 2017ZX10203205

Award Recipient : Jianguo Wang Di Lu Xiao Xu

Funded by: FundRef https://doi.org/10.13039/501100008990, Science and Technology Department of Zhejiang Province;

Award ID: 2019C03050

Award Recipient : Xiaonan Xiang Jianguo Wang Di Lu Xiao Xu

Funded by: FundRef https://doi.org/10.13039/501100005153, China National Funds for Distinguished Young Scientists;

Award ID: 81625003

Award Recipient : Jianguo Wang Di Lu

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 81801824

Award Recipient : Jianguo Wang

Funded by: FundRef https://doi.org/10.13039/501100010903, National Science Foundation of China | Key Programme;

Award ID: 81930016

Award Recipient : Di Lu

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Keywords: gastrointestinal cancer,immunotherapy,cancer microenvironment,tumour immunology

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Keywords: gastrointestinal cancer, immunotherapy, cancer microenvironment, tumour immunology

Targeting tumor-associated macrophages to synergize tumor immunotherapy

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Abstract

Related collections

Cancer Immunotherapy

Most cited references 170

The Immune Landscape of Cancer

Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

Oncology meets immunology: the cancer-immunity cycle.

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