Enhance the Immune Checkpoint Inhibitors Efficacy with Radiotherapy Induced Immunogenic Cell Death: A Comprehensive Review and Latest Developments

Procureur, Adrien; Simonaggio, Audrey; Bibault, Jean‐Emmanuel; Oudard, Stéphane; Vano, Yann-Alexandre

doi:10.3390/cancers13040678

Cited by 37 publications

(35 citation statements)

References 96 publications

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“…Procureur et al. has recently published an excellent review about the enhancement of ICIs by radiotherapy-induced immunogenic cell death ( 157 ). Radiotherapy-induced systemic immune activation could cause shrinkage of distant tumor lesions outside the irradiated field, a phenomenon known as abscopal effect ( 158 ).…”

Section: Novel Strategies To Potentiate Pd-1/pd-l1 Blockade Immunotherapy In Egfr Mutant Nsclcmentioning

confidence: 99%

“…Irradiation is known to activate host immunity by triggering ICD, which is characterized by the release of DAMPs to activate dendritic cells and to prime antigen-specific T cells in a dosedependent manner(156). Procureur et al has recently published an excellent review about the enhancement of ICIs by radiotherapy-induced immunogenic cell death(157). Radiotherapy-induced systemic immune activation could cause shrinkage of distant tumor lesions outside the irradiated field, a phenomenon known as abscopal effect…”

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confidence: 99%

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Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies

Fong

Cho

2021

Front. Oncol.

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Lung cancer is the leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors, including monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), have dramatically improved the survival and quality of life of a subset of non-small cell lung cancer (NSCLC) patients. Multiple predictive biomarkers have been proposed to select the patients who may benefit from the immune checkpoint inhibitors. EGFR-mutant NSCLC is the most prevalent molecular subtype in Asian lung cancer patients. However, patients with EGFR-mutant NSCLC show poor response to anti-PD-1/PD-L1 treatment. While small-molecule EGFR tyrosine kinase inhibitors (TKIs) are the preferred initial treatment for EGFR-mutant NSCLC, acquired drug resistance is severely limiting the long-term efficacy. However, there is currently no further effective treatment option for TKIs-refractory EGFR-mutant NSCLC patients. The reasons mediating the poor response of EGFR-mutated NSCLC patients to immunotherapy are not clear. Initial investigations revealed that EGFR-mutated NSCLC has lower PD-L1 expression and a low tumor mutational burden, thus leading to weak immunogenicity. Moreover, the use of PD-1/PD-L1 blockade prior to or concurrent with osimertinib has been reported to increase the risk of pulmonary toxicity. Furthermore, emerging evidence shows that PD-1/PD-L1 blockade in NSCLC patients can lead to hyperprogressive disease associated with dismal prognosis. However, it is difficult to predict the treatment toxicity. New biomarkers are urgently needed to predict response and toxicity associated with the use of PD-1/PD-L1 immunotherapy in EGFR-mutated NSCLC. Recently, promising data have emerged to suggest the potentiation of PD-1/PD-L1 blockade therapy by anti-angiogenic agents and a few other novel therapeutic agents. This article reviews the current investigations about the poor response of EGFR-mutated NSCLC to anti-PD-1/PD-L1 therapy, and discusses the new strategies that may be adopted in the future.

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Section: Novel Strategies To Potentiate Pd-1/pd-l1 Blockade Immunotherapy In Egfr Mutant Nsclcmentioning

confidence: 99%

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confidence: 99%

Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies

Fong

Cho

2021

Front. Oncol.

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“…Interestingly, very recent data reveal that somewhat similar results may be obtained with conventional RT in combination with DNA repair and immune checkpoint inhibitors [ 501 , 504 , 505 , 506 ] and also with the new evolving technique using high intensity short FLASH IR exposures [ 507 , 508 , 509 , 510 , 511 , 512 ]. Moreover, these approaches were also able to attenuate inflammatory and fibrotic responses as well as the formation of metastasis and secondary cancers.…”

Section: Discussionmentioning

confidence: 82%

Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts

Averbeck

Rodriguez-Lafrasse

2021

IJMS

100

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Until recently, radiation effects have been considered to be mainly due to nuclear DNA damage and their management by repair mechanisms. However, molecular biology studies reveal that the outcomes of exposures to ionizing radiation (IR) highly depend on activation and regulation through other molecular components of organelles that determine cell survival and proliferation capacities. As typical epigenetic-regulated organelles and central power stations of cells, mitochondria play an important pivotal role in those responses. They direct cellular metabolism, energy supply and homeostasis as well as radiation-induced signaling, cell death, and immunological responses. This review is focused on how energy, dose and quality of IR affect mitochondria-dependent epigenetic and functional control at the cellular and tissue level. Low-dose radiation effects on mitochondria appear to be associated with epigenetic and non-targeted effects involved in genomic instability and adaptive responses, whereas high-dose radiation effects (>1 Gy) concern therapeutic effects of radiation and long-term outcomes involving mitochondria-mediated innate and adaptive immune responses. Both effects depend on radiation quality. For example, the increased efficacy of high linear energy transfer particle radiotherapy, e.g., C-ion radiotherapy, relies on the reduction of anastasis, enhanced mitochondria-mediated apoptosis and immunogenic (antitumor) responses.

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“…Conventional radiotherapy and chemotherapy have been attributed to eliciting DNA damage. Emerging evidence has shown that chemoradiation or radiation "boosts" the cancer immunotherapy response (122,123). Radiotherapy has been shown to enhance cancer immunotherapy, leading to more than 100 clinical trials of radiation and immunotherapy combinations across cancer types (124)(125)(126).…”

Section: Radiation and Immunotherapymentioning

confidence: 99%

“…Radiotherapy has been shown to enhance cancer immunotherapy, leading to more than 100 clinical trials of radiation and immunotherapy combinations across cancer types (124)(125)(126). The main rationale of developing cancer radioimmunotherapy is the "boost" of the immune response by radiation via several mechanisms (122). First, due to the intrinsic defects of cancer cells in cell cycle checkpoints, DNA damage checkpoints, DNA replication checkpoints, and mitotic checkpoints (also called spindle assembly checkpoints), irradiated tumor cells with unrepaired and/or incompletely replicated DNA result in cytoplasmic DNA fragments and micronuclei, which activate cGAS/STING signaling.…”

Section: Radiation and Immunotherapymentioning

confidence: 99%

Narrative review of emerging roles for AKT-mTOR signaling in cancer radioimmunotherapy

Shen

Chen

et al. 2021

Ann Transl Med

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Objective: To summarize the roles of AKT-mTOR signaling in the regulation of the DNA damage response and PD-L1 expression in cancer cells, and propose a novel strategy of targeting AKT-mTOR signaling in combination with radioimmunotherapy in the era of cancer immunotherapy Background: Immunotherapy has greatly improved the clinical outcomes of many cancer patients and has changed the landscape of cancer patient management. However, only a small subgroup of cancer patients (~20-30%) benefit from immune checkpoint blockade-based immunotherapy. The current challenge is to find biomarkers to predict the response of patients to immunotherapy and strategies to sensitize patients to immunotherapy.Methods: Search and review the literature which were published in PUBMED from 2000-2021 with the key words mTOR, AKT, drug resistance, DNA damage response, immunotherapy, PD-L1, DNA repair, radioimmunotherapy.Conclusions: More than 50% of cancer patients receive radiotherapy during their course of treatment.Radiotherapy has been shown to reduce the growth of locally irradiated tumors as well as metastatic nonirradiated tumors (abscopal effects) by affecting systemic immunity. Consistently, immunotherapy has been demonstrated to enhance radiotherapy with more than one hundred clinical trials of radiation in combination with immunotherapy (radioimmunotherapy) across cancer types. Nevertheless, current available data have shown limited efficacy of trials testing radioimmunotherapy. AKT-mTOR signaling is a major tumor growth-promoting pathway and is upregulated in most cancers. AKT-mTOR signaling is activated by growth factors as well as genotoxic stresses including radiotherapy. Importantly, recent advances have shown that AKT-mTOR is one of the main signaling pathways that regulate DNA damage repair as well as PD-L1 levels in cancers. These recent advances clearly suggest a novel cancer therapy strategy by targeting AKT-mTOR signaling in combination with radioimmunotherapy.

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Enhance the Immune Checkpoint Inhibitors Efficacy with Radiotherapy Induced Immunogenic Cell Death: A Comprehensive Review and Latest Developments

Cited by 37 publications

References 96 publications

Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies

Immunotherapy in Treating EGFR-Mutant Lung Cancer: Current Challenges and New Strategies

Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts

Narrative review of emerging roles for AKT-mTOR signaling in cancer radioimmunotherapy

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