Impact of DNA Damage Response on Anti-tumor Immunity

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43

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articles

Editorial

27 September 2022

Editorial: The impact of the DNA damage response on anti-tumor immunity

Gang Chen

,

Shengtao Zhou

,

Chaoyang Sun

and

Leng Han

1,686 views

1 citations

Editors

4

Huazhong University of Science and Technology

West China Second University Hospital, Sichuan University

Huazhong University of Science and Technology

University of Texas Health Science Center at Houston

Impact

Review

03 January 2022

The cGAS/STING Pathway: A Novel Target for Cancer Therapy

Yu Gan

, 6 more and

Wei Li

In the presence of various cytoplasmic DNAs, as a natural immunosensor, cGAS can bind to dsDNA to form a 2:2 cGAS-dsDNA complex, generating a second messenger cGAMP, which activates the STING protein at the endoplasmic reticulum. STING is then transferred from the endoplasmic reticulum via ERGIC to the Golgi apparatus, palmitoylated at two cysteine residues Cys88 and Cys91. Modified STING recruits TBK1 and IRF3. At the same time, STING also binds and stimulates IKK, triggering the transcriptional activation of NF-kB. Ultimately, it regulates the expression and secretion of pro-inflammatory cytokines such as IFN. Binding of IFN to IFNAR1/IFNAR2 activates JAK1, phosphorylates STAT, and induces the expression of ISG. Created with BioRender.com.

As a DNA receptor, cyclic GMP-AMP synthase (cGAS) plays a crucial role in the immune system by recognizing abnormal DNA in the cytoplasm and activating the stimulator of interferon genes (STING) signaling pathway. This signaling cascade reaction leads to an immune response produced by type I interferon and other immune mediators. Recent advances in research have enhanced our current understanding of the potential role of the cGAS/STING pathway in anticancer therapy; however, in some cases, chronic STING activation may promote tumorigenesis. The present review article discusses the biological mechanisms of the cGAS/STING pathway, its dichotomous role in tumors, and the latest advances with respect to STING agonists and antagonists.

32,968 views

99 citations

(A) Kaplan-Meier overall survival curve for patients in the low and high DDR signature score groups. The survival difference was detected by log-rank test. (B) Time-dependent ROC curves for the composite model, DDR pathway signature model, and TNM classification model. (C) Calibration curves of observed and predicted probabilities of the composite model for 3-year, 5-year, and 10-year overall survival. (D) Composite nomogram prediction of 3-year, 5-year, and 10-year overall survival. (E) DCA curves of the composite model, DDR pathway signature model, and TNM classification model for 3-year, 5-year, and 10-year overall survival.

Original Research

10 January 2022

Patient-Level DNA Damage Repair Pathway Profiles and Anti-Tumor Immunity for Gastric Cancer

Shenghan Lou

, 5 more and

Yingwei Xue

5,830 views

14 citations

Article Cover Image

Review

12 October 2021

Targeting DNA Repair Response Promotes Immunotherapy in Ovarian Cancer: Rationale and Clinical Application

Hongyu Xie

, 3 more and

Bairong Xia

5,435 views

8 citations

Article Cover Image

Original Research

24 September 2021

Comutations in DDR Pathways Predict Atezolizumab Response in Non-Small Cell Lung Cancer Patients

Anning Xiong

, 9 more and

Xueyan Zhang

4,221 views

9 citations

Article Cover Image

Original Research

18 June 2021

Activation of the DDR Pathway Leads to the Down-Regulation of the TGFβ Pathway and a Better Response to ICIs in Patients With Metastatic Urothelial Carcinoma

Chaozheng Zhou

, 7 more and

Peng Luo

5,559 views

27 citations

Open for submission

Frontiers in Oncology

Advances in Immunosuppressive Microenvironment Remodeling and Targeted Drug Intervention in Pancreatic Cancer

Edited by Wei Zhao, Sarah Young, Qiaoling Song

Deadline

01 June 2025

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About

Drugs targeting DNA damage repair (DDR) are increasingly applied in anti-tumor therapies. DDR inhibition can induce and amplify DNA damage in cancer cells, with a deep impact on antitumor immune responses. Preclinical studies have shown that in addition to the direct poisonous effect on cancer cells, DDR-targeted drugs are also associated with increased tumor infiltrating lymphocytes, higher genomic instability, and higher tumor mutational burden (TMB) in cancer, enhancing the antitumor immune effect. This antitumor immune response can activate a long-lasting protective effect and help eliminate the residual cancer cells or maintain the metastases in a dormancy state. High quality studies on the mechanisms and translational research of immunological changes during DDR-targeted therapy will enable us to better understand the consequences of DDR-associated therapies in patients and ultimately benefit clinical practice.

This Research Topic aims at investigating the effects of DDR drugs on tumor immune microenvironment and immunogenic properties of tumor cells, in particular the molecular mechanisms that enhance antitumor immunity. For example, how DDR inhibitors can enhance the inflammatory IFN response to obtain a stronger anti-tumor effect, and the mechanisms underlying sustained anti-immune response caused by DDR-targeted drugs. Our ultimate goal is to support the development of combination therapies with DDR inhibitors and immune therapy to achieve stronger and more durable responses.

We welcome submissions of Original Research, Clinical Trial, Review, and Case Report on the following sub-themes:

• The relationship between DDR targeted therapies and patients’ response to immune checkpoint blockade (ICB) agents, as well as the immune-activating properties of DDR targeted therapies.
• Role of DNA repair defects (including DDR gene mutations, genomic instability and expression profile of DDR genes) in predicting immunotherapy response.
• The mechanisms of chemotherapy, radiation and DDR targeted therapy induced immunogenicity, including the cytosolic DNA sensing cGAS/STING-IFN pathway, neoantigen or tumor-associated antigen.
• The spatiotemporal and sequential treatment strategies for patients who are candidates for combination therapies with DDR inhibitors and immune therapy.
• Identification of novel DDR targets and combination strategies.
• Clinical update on the combination of DDR inhibitor and immunotherapy results and future perspectives.

Drugs targeting DNA damage repair (DDR) are increasingly applied in anti-tumor therapies. DDR inhibition can induce and amplify DNA damage in cancer cells, with a deep impact on antitumor immune responses. Preclinical studies have shown that in addition to the direct poisonous effect on cancer cells, DDR-targeted drugs are also associated with increased tumor infiltrating lymphocytes, higher genomic instability, and higher tumor mutational burden (TMB) in cancer, enhancing the antitumor immune effect. This antitumor immune response can activate a long-lasting protective effect and help eliminate the residual cancer cells or maintain the metastases in a dormancy state. High quality studies on the mechanisms and translational research of immunological changes during DDR-targeted therapy will enable us to better understand the consequences of DDR-associated therapies in patients and ultimately benefit clinical practice.

This Research Topic aims at investigating the effects of DDR drugs on tumor immune microenvironment and immunogenic properties of tumor cells, in particular the molecular mechanisms that enhance antitumor immunity. For example, how DDR inhibitors can enhance the inflammatory IFN response to obtain a stronger anti-tumor effect, and the mechanisms underlying sustained anti-immune response caused by DDR-targeted drugs. Our ultimate goal is to support the development of combination therapies with DDR inhibitors and immune therapy to achieve stronger and more durable responses.

We welcome submissions of Original Research, Clinical Trial, Review, and Case Report on the following sub-themes:

• The relationship between DDR targeted therapies and patients’ response to immune checkpoint blockade (ICB) agents, as well as the immune-activating properties of DDR targeted therapies.
• Role of DNA repair defects (including DDR gene mutations, genomic instability and expression profile of DDR genes) in predicting immunotherapy response.
• The mechanisms of chemotherapy, radiation and DDR targeted therapy induced immunogenicity, including the cytosolic DNA sensing cGAS/STING-IFN pathway, neoantigen or tumor-associated antigen.
• The spatiotemporal and sequential treatment strategies for patients who are candidates for combination therapies with DDR inhibitors and immune therapy.
• Identification of novel DDR targets and combination strategies.
• Clinical update on the combination of DDR inhibitor and immunotherapy results and future perspectives.

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Editors

Huazhong University of Science and Technology

West China Second University Hospital, Sichuan University

Huazhong University of Science and Technology

University of Texas Health Science Center at Houston

Impact

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32,836 Article views

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Frontiers in Immunology

Cancer Immunity and Immunotherapy

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Frontiers in Pharmacology

Pharmacology of Anti-Cancer Drugs

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Frontiers in Oncology

Pharmacology of Anti-Cancer Drugs, Cancer Immunity and Immunotherapy

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