Double-edged effects of interferons on the regulation of cancer-immunity cycle

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ABSTRACT

Interferons (IFNs) are a large family of pleiotropic cytokines that regulate both innate and adaptive immunity and show anti-cancer effects in various cancer types. Moreover, it was revealed that IFN signaling plays critical roles in the success of cancer therapy strategies, thereby enhancing their therapeutic effects. However, IFNs have minimal or even adverse effects on cancer eradication, and mediate cancer immune escape in some instances. Thus, IFNs have a double-edged effect on the cancer immune response. Recent studies suggest that IFNs regulate each step of the cancer immunity-cycle, consisting of cancer antigen release, presentation of antigens and activation of T cells, trafficking and infiltration of effector T cells into the tumor microenvironment, and recognition and killing of cancer cells, which contributes to our understanding of the mechanisms of IFNs in regulating cancer immunity. In this review, we focus on IFNs and cancer immunity and elaborate on the roles of IFNs in regulating the cancer-immunity cycle.

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Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion.

Robert D. Schreiber, Lloyd J. Old, Mark J. Smyth (2011)

Understanding how the immune system affects cancer development and progression has been one of the most challenging questions in immunology. Research over the past two decades has helped explain why the answer to this question has evaded us for so long. We now appreciate that the immune system plays a dual role in cancer: It can not only suppress tumor growth by destroying cancer cells or inhibiting their outgrowth but also promote tumor progression either by selecting for tumor cells that are more fit to survive in an immunocompetent host or by establishing conditions within the tumor microenvironment that facilitate tumor outgrowth. Here, we discuss a unifying conceptual framework called "cancer immunoediting," which integrates the immune system's dual host-protective and tumor-promoting roles.

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CD8 + T cells regulate tumor ferroptosis during cancer immunotherapy

Weimin Wang, Michael Green, Jae Eun Choi … (2019)

Summary Cancer immunotherapy restores and/or enhances effector function of CD8+ T cells in the tumor microenvironment 1,2 . CD8+ T cells activated by cancer immunotherapy execute tumor clearance mainly by inducing cell death through perforin-granzyme- and Fas/Fas ligand-pathways 3,4 . Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent lipid peroxide accumulation 5,6 . Although it was mechanistically illuminated in vitro 7,8 , emerging evidence has shown that ferroptosis may be implicated in a variety of pathological scenarios 9,10 . However, the involvement of ferroptosis in T cell immunity and cancer immunotherapy is unknown. Here, we find that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumor cells, and in turn, increased ferroptosis contributes to the anti-tumor efficacy of immunotherapy. Mechanistically, interferon gamma (IFNγ) released from CD8+ T cells downregulates expression of SLC3A2 and SLC7A11, two subunits of glutamate-cystine antiporter system xc-, restrains tumor cell cystine uptake, and as a consequence, promotes tumor cell lipid peroxidation and ferroptosis. In preclinical models, depletion of cyst(e)ine by cyst(e)inase in combination with checkpoint blockade synergistically enhances T cell-mediated anti-tumor immunity and induces tumor cell ferroptosis. Expression of system xc- is negatively associated with CD8+ T cell signature, IFNγ expression, and cancer patient outcome. Transcriptome analyses before and during nivolumab therapy reveal that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNγ and CD8. Thus, T cell-promoted tumor ferroptosis is a novel anti-tumor mechanism. Targeting tumor ferroptosis pathway constitutes a therapeutic approach in combination with checkpoint blockade.

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NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control

Jan Böttcher, Eduardo Bonavita, Probir Chakravarty … (2018)

Summary Conventional type 1 dendritic cells (cDC1) are critical for antitumor immunity, and their abundance within tumors is associated with immune-mediated rejection and the success of immunotherapy. Here, we show that cDC1 accumulation in mouse tumors often depends on natural killer (NK) cells that produce the cDC1 chemoattractants CCL5 and XCL1. Similarly, in human cancers, intratumoral CCL5, XCL1, and XCL2 transcripts closely correlate with gene signatures of both NK cells and cDC1 and are associated with increased overall patient survival. Notably, tumor production of prostaglandin E2 (PGE2) leads to evasion of the NK cell-cDC1 axis in part by impairing NK cell viability and chemokine production, as well as by causing downregulation of chemokine receptor expression in cDC1. Our findings reveal a cellular and molecular checkpoint for intratumoral cDC1 recruitment that is targeted by tumor-derived PGE2 for immune evasion and that could be exploited for cancer therapy.

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Author and article information

Journal

Journal ID (nlm-ta): Oncoimmunology

Journal ID (iso-abbrev): Oncoimmunology

Title: Oncoimmunology

Publisher: Taylor & Francis

ISSN (Print): 2162-4011

ISSN (Electronic): 2162-402X

Publication date (Electronic, pub): 30 June 2021

Publication date (Electronic, collection): 2021

Publication date PMC-release: 30 June 2021

Volume: 10

Issue: 1

Electronic Location Identifier: 1929005

Affiliations

[a ]Department of Stomatology, Shenzhen Second People’s Hospital, the First Affiliated Hospital of Shenzhen University; , Shenzhen, China

[b ]Department of Pathology, Harbin Medical University; , Harbin, China

[c ]Department of Oncology, Chifeng City Hospital; , Chifeng, China

[d ]Department of Stomatology, the PeopIe’s Hospital of Longhua; , Shenzhen, China

[e ]Department of Stomatology, Affiliated Zhongshan Hospital of Dalian University; , Dalian, China

Author notes

CONTACT Xiaobo Li lixiaobo@ 123456ems.hrbmu.edu.cn Department of Pathology, Harbin Medical University; , No. 157 Baojian Road, Nangang District, Harbin, 150081, China

Qiuxu wang 1085779616@ 123456qq.com the First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital; , No.3002 Sungangxi Road, Shenzhen, 518000, China.

[#]

These authors contributed equally to this work.

Article

Publisher ID: 1929005

DOI: 10.1080/2162402X.2021.1929005

PMC ID: 8253121

PubMed ID: 34262796

SO-VID: a1078195-ee00-4ade-bd60-edfd98cb093a

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This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Double-edged effects of interferons on the regulation of cancer-immunity cycle

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Cancer Immunotherapy

Most cited references 240

Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion.

CD8 + T cells regulate tumor ferroptosis during cancer immunotherapy

NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control

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