Endogenous Retrovirus Activation as a Key Mechanism of Anti-Tumor Immune Response in Radiotherapy

Lee, Andrew K.; Pan, Dong; Bao, Xiaoyong; Hu, Mengjie; Li, Fang; Li, Chuan-Yuan

doi:10.1667/rade-20-00013

Cited by 41 publications

(36 citation statements)

References 69 publications

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“…Recently, Lee AK. et al [ 41 ] have demonstrated that TRIM28 affected intratumoral lymphocyte infiltration in melanoma patients. Higher levels of TRIM28 negatively correlated with different immune effector subsets as determined using the CIBERSORT.…”

Section: Discussionmentioning

confidence: 99%

Melanoma Stem Cell-Like Phenotype and Significant Suppression of Immune Response within a Tumor Are Regulated by TRIM28 Protein

Czerwińska

Jaworska

Wlodarczyk

et al. 2020

Cancers

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TRIM28 emerged as a guard of the intrinsic “state of cell differentiation”, facilitating self-renewal of pluripotent stem cells. Recent reports imply TRIM28 engagement in cancer stem cell (CSC) maintenance, although the exact mechanism remains unresolved. TRIM28 high expression is associated with worse melanoma patient outcomes. Here, we investigated the association between TRIM28 level and melanoma stemness, and aligned it with the antitumor immune response to find the mechanism of “stemness high/immune low” melanoma phenotype acquisition. Based on the SKCM TCGA data, the TRIM28 expression profile, clinicopathological features, expression of correlated genes, and the level of stemness and immune scores were analyzed in patient samples. The biological function for differentially expressed genes was annotated with GSEA. Results were validated with additional datasets from R2: Genomics Analysis and Visualization Platform and in vitro with a panel of seven melanoma cell lines. All statistical analyses were accomplished using GraphPad Prism 8. TRIM28HIGH-expressing melanoma patients are characterized by worse outcomes and significantly different gene expression profiles than the TRIM28NORM cohort. TRIM28 high level related to higher melanoma stemness as measured with several distinct scores and TRIM28HIGH-expressing melanoma cell lines possess the greater potential of melanosphere formation. Moreover, TRIM28HIGH melanoma tumors were significantly depleted with infiltrating immune cells, especially cytotoxic T cells, helper T cells, and B cells. Furthermore, TRIM28 emerged as a good predictor of “stemness high/immune low” melanoma phenotype. Our data indicate that TRIM28 might facilitate this phenotype by direct repression of interferon signaling. TRIM28 emerged as a direct link between stem cell-like phenotype and attenuated antitumor immune response in melanoma, although further studies are needed to evaluate the direct mechanism of TRIM28-mediated stem-like phenotype acquisition.

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Section: Discussionmentioning

confidence: 99%

Melanoma Stem Cell-Like Phenotype and Significant Suppression of Immune Response within a Tumor Are Regulated by TRIM28 Protein

Czerwińska

Jaworska

Wlodarczyk

et al. 2020

Cancers

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“…Similar to RIG-I, melanoma differentiation-associated protein 5 (MDA5) is a cytoplasmic RNA sensor and upstream regulator of MAVS signaling. IR increased levels of cytosolic dsRNA derived from endogenous retrovirus activation, which induced interferon-stimulated genes through MDA5-MAVS signaling [ 100 ]. In summary, the exact contribution of MAVS- and/or STING-mediated type I IFN production post-IR treatment remains to be elucidated, however both pathways may play a role in inducing type I IFNs following radiotherapy.…”

Section: Sting-independent Activation Of Type I Interferons Followmentioning

confidence: 99%

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

Storozynsky

Hitt

2020

IJMS

124

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Radiotherapy is a major modality used to combat a wide range of cancers. Classical radiobiology principles categorize ionizing radiation (IR) as a direct cytocidal therapeutic agent against cancer; however, there is an emerging appreciation for additional antitumor immune responses generated by this modality. A more nuanced understanding of the immunological pathways induced by radiation could inform optimal therapeutic combinations to harness radiation-induced antitumor immunity and improve treatment outcomes of cancers refractory to current radiotherapy regimens. Here, we summarize how radiation-induced DNA damage leads to the activation of a cytosolic DNA sensing pathway mediated by cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING). The activation of cGAS–STING initiates innate immune signaling that facilitates adaptive immune responses to destroy cancer. In this way, cGAS–STING signaling bridges the DNA damaging capacity of IR with the activation of CD8+ cytotoxic T cell-mediated destruction of cancer—highlighting a molecular pathway radiotherapy can exploit to induce antitumor immune responses. In the context of radiotherapy, we further report on factors that enhance or inhibit cGAS–STING signaling, deleterious effects associated with cGAS–STING activation, and promising therapeutic candidates being investigated in combination with IR to bolster immune activation through engaging STING-signaling. A clearer understanding of how IR activates cGAS–STING signaling will inform immune-based treatment strategies to maximize the antitumor efficacy of radiotherapy, improving therapeutic outcomes.

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“…For example, the cGAS/STING pathway was shown to be critical for ICB therapy and radiotherapy in preclinical models (12)(13)(14)(15). On the other hand, the RIG-1/MDA5 pathway was shown to be activated by endogenous retroviruses, which could be activated by DNA methyltransferase inhibitors and synergize with ICB therapy (16,17), and radiotherapy (18). Therefore, there are many efforts in trying to activate those innate inflammatory signaling pathways in the tumor microenvironment to enhance ICB therapy.…”

Section: Introductionmentioning

confidence: 99%

ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage and cGAS/STING activation

Hu¹,

Zhou²,

Bao³

et al. 2021

Journal of Clinical Investigation

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148

113

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Endogenous Retrovirus Activation as a Key Mechanism of Anti-Tumor Immune Response in Radiotherapy

Cited by 41 publications

References 69 publications

Melanoma Stem Cell-Like Phenotype and Significant Suppression of Immune Response within a Tumor Are Regulated by TRIM28 Protein

Melanoma Stem Cell-Like Phenotype and Significant Suppression of Immune Response within a Tumor Are Regulated by TRIM28 Protein

The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer

ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage and cGAS/STING activation

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