The role of radiotherapy in the age of immunotherapy

Sato, Hiro; Demaria, Sandra; Ohno, Tatsuya

doi:10.1093/jjco/hyaa268

Cited by 32 publications

(19 citation statements)

References 69 publications

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“…A randomized phase 3 PACIFIC study showed that consolidation therapy with an anti-programmed death ligand-1 antibody prolongs survival of patients with locally advanced non-small cell lung cancer treated with chemo-radiotherapy [4]. In addition, a number of clinical trials are underway to test the efficacy of the ICI-radiotherapy combination against various cancers [5].…”

Section: Introductionmentioning

confidence: 99%

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High tumor mutational burden predicts worse prognosis for cervical cancer treated with radiotherapy

et al. 2021

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Purpose Tumor mutational burden (TMB) is a surrogate biomarker of neo-antigens and high TMB status is associated with favorable response to immune-checkpoint inhibitors (ICIs). This study aimed to elucidate the association between TMB and the outcome of definitive radiotherapy in patients with cervical cancer. Materials and methods TMB and treatment outcome were retrospectively analyzed in patients with newly diagnosed cervical cancer treated with definitive radiotherapy available with somatic mutation data of pre-treatment tumors obtained using a commercially available gene panel. Results The study enrolled 98 patients (median follow-up period, 61 months). The median TMB was 9.5 mutations per megabase (range, 3.0–35.5 mutations per megabase). After dichotomization based on this median value, the 5-year overall survival (OS) for TMB-high patients was significantly worse than that of TMB-low patients (61.1% vs. 82.2%). Multivariate analysis identified high TMB status as a significant prognostic factor for worse OS, along with advanced stage, para-aortic lymph node involvement, and absence of concurrent chemotherapy. Conclusion These data indicate that TMB is a potential prognostic factor for worse survival in patients with cervical cancer treated with definitive radiotherapy, thereby providing a rationale for treatment of TMB-high cervical cancers with a combination of ICIs plus radiotherapy. Secondary abstract This retrospective study of 98 patients demonstrates for the first time that tumor mutational burden (TMB) is an independent prognostic factor for worse overall survival of patients treated with definitive radiotherapy, providing a rationale for treatment of TMB-high cervical cancers with a combination of immune-checkpoint inhibitors plus radiotherapy.

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Section: Introductionmentioning

confidence: 99%

“…Accumulating evidence suggests that ionizing radiation (IR) induces antitumor immune responses [5]. When a tumor is irradiated, neo-antigens are released by dying tumor cells [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

High tumor mutational burden predicts worse prognosis for cervical cancer treated with radiotherapy

et al. 2021

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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: 81%

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

Averbeck

Rodriguez-Lafrasse

2021

IJMS

110

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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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“…ICD can be considered a mainstay of the abscopal effect triggered by local treatment with ionizing radiation. The concept of ICD that emerged at the beginning of this century [ 246 ] was recently reviewed as a general phenomenon [ 247 ] and in relationship to RT [ 248 ] (for consensus guidelines see Ref. [ 249 ]).…”

Section: Immunogenic Cell Deathmentioning

confidence: 99%

Abscopal Effect and Drug-Induced Xenogenization: A Strategic Alliance in Cancer Treatment?

Franzese

Torino

Giannetti

et al. 2021

IJMS

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The current state of cancer treatment is still far from being satisfactory considering the strong impairment of patients’ quality of life and the high lethality of malignant diseases. Therefore, it is critical for innovative approaches to be tested in the near future. In view of the crucial role that is played by tumor immunity, the present review provides essential information on the immune-mediated effects potentially generated by the interplay between ionizing radiation and cytotoxic antitumor agents when interacting with target malignant cells. Therefore, the radiation-dependent abscopal effect (i.e., a biological effect of ionizing radiation that occurs outside the irradiated field), the influence of cancer chemotherapy on the antigenic pattern of target neoplastic cells, and the immunogenic cell death (ICD) caused by anticancer agents are the main topics of this presentation. It is widely accepted that tumor immunity plays a fundamental role in generating an abscopal effect and that anticancer drugs can profoundly influence not only the host immune responses, but also the immunogenic pattern of malignant cells. Remarkably, several anticancer drugs impact both the abscopal effect and ICD. In addition, certain classes of anticancer agents are able to amplify already expressed tumor-associated antigens (TAA). More importantly, other drugs, especially triazenes, induce the appearance of new tumor neoantigens (TNA), a phenomenon that we termed drug-induced xenogenization (DIX). The adoption of the abscopal effect is proposed as a potential therapeutic modality when properly applied concomitantly with drug-induced increase in tumor cell immunogenicity and ICD. Although little to no preclinical or clinical studies are presently available on this subject, we discuss this issue in terms of potential mechanisms and therapeutic benefits. Upcoming investigations are aimed at evaluating how chemical anticancer drugs, radiation, and immunotherapies are interacting and cooperate in evoking the abscopal effect, tumor xenogenization and ICD, paving the way for new and possibly successful approaches in cancer therapy.

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The role of radiotherapy in the age of immunotherapy

Cited by 32 publications

References 69 publications

High tumor mutational burden predicts worse prognosis for cervical cancer treated with radiotherapy

High tumor mutational burden predicts worse prognosis for cervical cancer treated with radiotherapy

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

Abscopal Effect and Drug-Induced Xenogenization: A Strategic Alliance in Cancer Treatment?

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