Error‐prone <scp>DNA</scp> repair pathways as determinants of immunotherapy activity: an emerging scenario for cancer treatment

Caracciolo, Daniele; Riillo, Caterina; Arbitrio, Mariamena; Martino, Maria Teresa Di; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

doi:10.1002/ijc.33038

Cited by 14 publications

(10 citation statements)

References 121 publications

(186 reference statements)

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“…It should be noted that although MSI-H/dMMR is associated with TMB-H, DDR genes are still associated with a high TMB after MSI-H/dMMR is excluded [ 69 ]. As for the relationship between NAL and TMB, previous studies have proven that high TMB can cause an increase in neoantigens [ 137 ].…”

Section: The Mechanism Of Altered Ddr Pathway Affecting the Efficacy ...mentioning

confidence: 99%

“…DDR pathway dysfunction in tumors is capable of activating an immune response, reshaping the immune environment, and is ultimately beneficial to the effectiveness of ICIs. The primary mechanisms involved can be described as follows: (1) increasing the level of neoantigen and tumor immunogenicity, which is beneficial to the immune recognition process in antigen presentation; (2) the activated cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway triggers innate immunity and enhances the recruitment and tumor infiltration of T cells; (3) ATM/ataxia telangiectasia and Rad3-related protein (ATR)/Chk1 signals cascade to regulate the tumor microenvironment (TME), such as up-regulating PD-L1; and (4) other ways to enhance immunogenic cell death that help activate adaptive immunity [51,76,136,137].…”

Section: The Mechanism Of Altered Ddr Pathway Affecting the Efficacy ...mentioning

confidence: 99%

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The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy

Shi

Qin

Lin

et al. 2022

J Exp Clin Cancer Res

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As our understanding of the mechanisms of cancer treatment has increased, a growing number of studies demonstrate pathways through which DNA damage repair (DDR) affects the immune system. At the same time, the varied response of patients to immune checkpoint blockade (ICB) therapy has prompted the discovery of various predictive biomarkers and the study of combination therapy. Here, our investigation explores the interactions involved in combination therapy, accompanied by a review that summarizes currently identified and promising predictors of response to immune checkpoint inhibitors (ICIs) that are useful for classifying oncology patients. In addition, this work, which discusses immunogenicity and several components of the tumor immune microenvironment, serves to illustrate the mechanism by which higher response rates and improved efficacy of DDR inhibitors (DDRi) in combination with ICIs are achieved.

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Section: The Mechanism Of Altered Ddr Pathway Affecting the Efficacy ...mentioning

confidence: 99%

Section: The Mechanism Of Altered Ddr Pathway Affecting the Efficacy ...mentioning

confidence: 99%

The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy

Shi

Qin

Lin

et al. 2022

J Exp Clin Cancer Res

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“…In fact, a chemotherapy-induced sensitization of tumor cells to the patient’s immune response triggered by subsequent ICB seems possible. Data supporting this hypothesis are based on clinical and experimental evidence that defects in the DNA repair machinery might play a decisive role in the activity of ICB [ 18 ]. Since adding the CTLA-4 inhibitor ipilimumab has already shown anti-tumor activity in PD-1-refractory patients with metastatic MCC [ 7 ], combined ICB according to the ongoing CheckMate-358 study (NCT02488759) seems to be a promising treatment option for avelumab-refractory patients.…”

Section: Discussionmentioning

confidence: 99%

Activity of ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma

Glutsch

Kneitz

Gesierich

et al. 2021

Cancer Immunol Immunother

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Background Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cutaneous malignancy with poor prognosis. In Europe, approved systemic therapies are limited to the PD-L1 inhibitor avelumab. For avelumab-refractory patients, efficient and safe treatment options are lacking. Methods At three different sites in Germany, clinical and molecular data of patients with metastatic MCC being refractory to the PD-L1 inhibitor avelumab and who were later on treated with combined IPI/NIVO were retrospectively collected and evaluated. Results Five patients treated at three different academic sites in Germany were enrolled. Three out of five patients investigated for this report responded to combined IPI/NIVO according to RECIST 1.1. Combined immunotherapy was well tolerated without any grade II or III immune-related adverse events. Two out of three responders to IPI/NIVO received platinum-based chemotherapy in between avelumab and combined immunotherapy. Conclusion In this small retrospective study, we observed a high response rate and durable responses to subsequent combined immunotherapy with IPI/NIVO in avelumab-refractory metastatic MCC patients. In conclusion, our data suggest a promising activity of second- or third-line PD-1- plus CTLA-4-blockade in patients with anti-PD-L1-refractory MCC.

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“…Inactivation of DNA repair pathways can lead to significant increase in tumor mutational burden ( 182 , 183 ). The contribution of DNA repair and replication processes to genomic instability under hypoxic conditions is clearly evident from the defective homologous recombination and defective mismatch repair related mutational signatures ( 171 ).…”

Section: The Hidden Potential Of Hypoxia-modulated Genetic Heterogene...mentioning

confidence: 99%

The Effect of Hypoxia and Hypoxia-Associated Pathways in the Regulation of Antitumor Response: Friends or Foes?

et al. 2022

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Hypoxia is an environmental stressor that is instigated by low oxygen availability. It fuels the progression of solid tumors by driving tumor plasticity, heterogeneity, stemness and genomic instability. Hypoxia metabolically reprograms the tumor microenvironment (TME), adding insult to injury to the acidic, nutrient deprived and poorly vascularized conditions that act to dampen immune cell function. Through its impact on key cancer hallmarks and by creating a physical barrier conducive to tumor survival, hypoxia modulates tumor cell escape from the mounted immune response. The tumor cell-immune cell crosstalk in the context of a hypoxic TME tips the balance towards a cold and immunosuppressed microenvironment that is resistant to immune checkpoint inhibitors (ICI). Nonetheless, evidence is emerging that could make hypoxia an asset for improving response to ICI. Tackling the tumor immune contexture has taken on an in silico, digitalized approach with an increasing number of studies applying bioinformatics to deconvolute the cellular and non-cellular elements of the TME. Such approaches have additionally been combined with signature-based proxies of hypoxia to further dissect the turbulent hypoxia-immune relationship. In this review we will be highlighting the mechanisms by which hypoxia impacts immune cell functions and how that could translate to predicting response to immunotherapy in an era of machine learning and computational biology.

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Error‐prone DNA repair pathways as determinants of immunotherapy activity: an emerging scenario for cancer treatment

Cited by 14 publications

References 121 publications

The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy

The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy

Activity of ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma

The Effect of Hypoxia and Hypoxia-Associated Pathways in the Regulation of Antitumor Response: Friends or Foes?

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