Short-course radiotherapy promotes pro-inflammatory macrophages via extracellular vesicles in human rectal cancer

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Abstract

Background

Tumor-associated macrophages (TAM) constitute the most abundant immune cells in the tumor stroma initiating pro-inflammatory (M1) or immunosuppressive (M2) responses depending on their polarization status. Advances in tumor immunotherapy call for a detailed understanding of potential immunogenic mechanisms of irradiation routinely applied in rectal cancer patients.

Methods

To test the effects of radiotherapy on TAM, we ex vivo irradiated tissue samples of human rectal cancer and assessed the phenotype by flow cytometry. We furthermore evaluated the distribution of leucocyte subsets in tissue sections of patients after short-course radiotherapy and compared findings to non-pretreated rectal cancer using an immunostaining approach. Organotypic assays (OTA) consisting of macrophages, cancer-associated fibroblast and cancer cell lines were used to dissect the immunological consequences of irradiation in macrophages.

Results

We demonstrate that short-course neoadjuvant radiotherapy in rectal cancer patients is associated with a shift in the polarization of TAM towards an M1-like pro-inflammatory phenotype. In addition, ex vivo irradiation caused an increase in the phagocytic activity and enhanced expression of markers associated with stimulatory signals necessary for T-cell activation. In OTA we observed that this alteration in macrophage polarization could be mediated by extracellular vesicles (EV) derived from irradiated tumor cells. We identified high mobility group box 1 in EV from irradiated tumor cells as a potential effector signal in that crosstalk.

Conclusions

Our findings highlight macrophages as potential effector cells upon irradiation in rectal cancer by diminishing their immunosuppressive phenotype and activate pro-inflammation. Our data indicate that clinically applied short-term radiotherapy for rectal cancer may be exploited to stimulate immunogenic macrophages and suggest to target the polarization status of macrophages to enhance future immunotherapeutic strategies.

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Most cited references 21

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HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses.

Hideyuki Yanai, Tatsuma Ban, ZhiChao Wang … (2009)

The activation of innate immune responses by nucleic acids is crucial to protective and pathological immunities and is mediated by the transmembrane Toll-like receptors (TLRs) and cytosolic receptors. However, it remains unknown whether a mechanism exists that integrates these nucleic-acid-sensing systems. Here we show that high-mobility group box (HMGB) proteins 1, 2 and 3 function as universal sentinels for nucleic acids. HMGBs bind to all immunogenic nucleic acids examined with a correlation between affinity and immunogenic potential. Hmgb1(-/-) and Hmgb2(-/-) mouse cells are defective in type-I interferon and inflammatory cytokine induction by DNA or RNA targeted to activate the cytosolic nucleic-acid-sensing receptors; cells in which the expression of all three HMGBs is suppressed show a more profound defect, accompanied by impaired activation of the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor (NF)-kappaB. The absence of HMGBs also severely impairs the activation of TLR3, TLR7 and TLR9 by their cognate nucleic acids. Our results therefore indicate a hierarchy in the nucleic-acid-mediated activation of immune responses, wherein the selective activation of nucleic-acid-sensing receptors is contingent on the more promiscuous sensing of nucleic acids by HMGBs. These findings may have implications for understanding the evolution of the innate immune system and for the treatment of immunological disorders.

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Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy.

Russell Hughes, Bin-Zhi Qian, Charlotte Rowan … (2015)

Tumor relapse after chemotherapy-induced regression is a major clinical problem, because it often involves inoperable metastatic disease. Tumor-associated macrophages (TAM) are known to limit the cytotoxic effects of chemotherapy in preclinical models of cancer. Here, we report that an alternatively activated (M2) subpopulation of TAMs (MRC1(+)TIE2(Hi)CXCR4(Hi)) accumulate around blood vessels in tumors after chemotherapy, where they promote tumor revascularization and relapse, in part, via VEGF-A release. A similar perivascular, M2-related TAM subset was present in human breast carcinomas and bone metastases after chemotherapy. Although a small proportion of M2 TAMs were also present in hypoxic tumor areas, when we genetically ablated their ability to respond to hypoxia via hypoxia-inducible factors 1 and 2, tumor relapse was unaffected. TAMs were the predominant cells expressing immunoreactive CXCR4 in chemotherapy-treated mouse tumors, with the highest levels expressed by MRC1(+) TAMs clustering around the tumor vasculature. Furthermore, the primary CXCR4 ligand, CXCL12, was upregulated in these perivascular sites after chemotherapy, where it was selectively chemotactic for MRC1(+) TAMs. Interestingly, HMOX-1, a marker of oxidative stress, was also upregulated in perivascular areas after chemotherapy. This enzyme generates carbon monoxide from the breakdown of heme, a gas known to upregulate CXCL12. Finally, pharmacologic blockade of CXCR4 selectively reduced M2-related TAMs after chemotherapy, especially those in direct contact with blood vessels, thereby reducing tumor revascularization and regrowth. Our studies rationalize a strategy to leverage chemotherapeutic efficacy by selectively targeting this perivascular, relapse-promoting M2-related TAM cell population.

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Reprogramming of Tumor-Associated Macrophages with Anticancer Therapies: Radiotherapy versus Chemo- and Immunotherapies

Géraldine Genard, Stéphane Lucas, Carine Michiels (2017)

Tumor-associated macrophages (TAMs) play a central role in tumor progression, metastasis, and recurrence after treatment. Macrophage plasticity and diversity allow their classification along a M1–M2 polarization axis. Tumor-associated macrophages usually display a M2-like phenotype, associated with pro-tumoral features whereas M1 macrophages exert antitumor functions. Targeting the reprogramming of TAMs toward M1-like macrophages would thus be an efficient way to promote tumor regression. This can be achieved through therapies including chemotherapy, immunotherapy, and radiotherapy (RT). In this review, we first describe how chemo- and immunotherapies can target TAMs and, second, we detail how RT modifies macrophage phenotype and present the molecular pathways that may be involved. The identification of irradiation dose inducing macrophage reprogramming and of the underlying mechanisms could lead to the design of novel therapeutic strategies and improve synergy in combined treatments.

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Author and article information

Journal

Journal ID (nlm-ta): J Immunother Cancer

Journal ID (iso-abbrev): J Immunother Cancer

Journal ID (hwp): jitc

Journal ID (publisher-id): jitc

Title: Journal for Immunotherapy of Cancer

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2051-1426

Publication date Collection: 2020

Publication date (Electronic): 18 August 2020

Volume: 8

Issue: 2

Electronic Location Identifier: e000667

Affiliations

[1 ]departmentDepartment of Visceral Surgery, Comprehensive Cancer Center , Medical University of Vienna , Vienna, Vienna, Austria

[2 ]departmentInstitute of Medical Genetics , Medical University of Vienna , Vienna, Vienna, Austria

[3 ]departmentDepartment of Pathology , Medical University of Vienna , Vienna, Vienna, Austria

[4 ]departmentDepartment of Dermatology , Medical University of Vienna , Vienna, Vienna, Austria

Author notes

[Correspondence to ] Dr. Michael Bergmann, MD; michael.bergmann@ 123456meduniwien.ac.at

Author information

Victoria Stary http://orcid.org/0000-0002-3854-9934

Brigitte Wolf http://orcid.org/0000-0003-2120-5614

Julia List http://orcid.org/0000-0002-4199-3198

Johannes Längle http://orcid.org/0000-0003-4771-1398

Andrea Beer http://orcid.org/0000-0002-0726-1233

Johanna Strobl http://orcid.org/0000-0003-3606-2185

Georg Stary http://orcid.org/0000-0003-1746-4250

Helmut Dolznig http://orcid.org/0000-0002-6063-3585

Michael Bergmann, MD http://orcid.org/0000-0001-8529-1166

Article

Publisher ID: jitc-2020-000667

DOI: 10.1136/jitc-2020-000667

PMC ID: 7437887

PubMed ID: 32817359

SO-VID: 4c349035-fcdc-4f1a-bbaa-e2450f1f16d1

License:

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

History

Date accepted : 02 July 2020

Funding

Funded by: the Comprehensive Cancer Center (CCC)-Grant, Vienna, Austria;

Award ID: no number available

Funded by: Austrian Federal Ministry of Education, Science and Research and the City of Vienna;

Award ID: no number available

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Keywords: macrophages,radiotherapy,tumor microenvironment

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Keywords: macrophages, radiotherapy, tumor microenvironment

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Short-course radiotherapy promotes pro-inflammatory macrophages via extracellular vesicles in human rectal cancer

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Abstract

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Bacterial extracellular vesicles

Most cited references 21

HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses.

Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy.

Reprogramming of Tumor-Associated Macrophages with Anticancer Therapies: Radiotherapy versus Chemo- and Immunotherapies

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Cited by 18

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