Effects of Radiation on the Tumor Microenvironment

Monjazeb, Arta M.; Schalper, Kurt A.; Villarroel‐Espíndola, Franz; Nguyen, Anthony T.; Shiao, Stephen L.; Young, Kristina H.

doi:10.1016/j.semradonc.2019.12.004

Cited by 43 publications

(32 citation statements)

References 165 publications

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“…Standard conventional doses (1-3 Gy fractions) increase vascular access and upregulate local production of cytokines and tumor cell surface expression of stress markers. 70 Hypofractionated moderate doses (eg, 8 Gy×3) elicit many of the effects of standard fractionation while producing a greater IFN-I response. 19 29 Finally, ablative doses (eg, 20 Gy/fx) lead to profound cell death while depleting radioresistant suppressive immune cells in the TME, but may also induce increased levels of fibrosis and chronic inflammatory/immune suppressive pathways (figure 5).…”

Section: Immune Modulatorsmentioning

confidence: 99%

Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose?

Demaria

Guha

Schoenfeld

et al. 2021

J Immunother Cancer

152

121

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Recent evidence indicates that ionizing radiation can enhance immune responses to tumors. Advances in radiation delivery techniques allow hypofractionated delivery of conformal radiotherapy. Hypofractionation or other modifications of standard fractionation may improve radiation’s ability to promote immune responses to tumors. Other novel delivery options may also affect immune responses, including T-cell activation and tumor-antigen presentation changes. However, there is limited understanding of the immunological impact of hypofractionated and unique multifractionated radiotherapy regimens, as these observations are relatively recent. Hence, these differences in radiotherapy fractionation result in distinct immune-modulatory effects. Radiation oncologists and immunologists convened a virtual consensus discussion to identify current deficiencies, challenges, pitfalls and critical gaps when combining radiotherapy with immunotherapy and making recommendations to the field and advise National Cancer Institute on new directions and initiatives that will help further development of these two fields.This commentary aims to raise the awareness of this complexity so that the need to study radiation dose, fractionation, type and volume is understood and valued by the immuno-oncology research community. Divergence of approaches and findings between preclinical studies and clinical trials highlights the need for evaluating the design of future clinical studies with particular emphasis on radiation dose and fractionation, immune biomarkers and selecting appropriate end points for combination radiation/immune modulator trials, recognizing that direct effect on the tumor and potential abscopal effect may well be different. Similarly, preclinical studies should be designed as much as possible to model the intended clinical setting. This article describes a conceptual framework for testing different radiation therapy regimens as separate models of how radiation itself functions as an immunomodulatory ‘drug’ to provide alternatives to the widely adopted ‘one-size-fits-all’ strategy of frequently used 8 Gy×3 regimens immunomodulation.

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Section: Immune Modulatorsmentioning

confidence: 99%

Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose?

Demaria

Guha

Schoenfeld

et al. 2021

J Immunother Cancer

152

121

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“…2 Prior studies examining the mechanistic underpinning of RT largely focused on the DNA-damaging properties and the resultant cell death; however, preclinical and clinical evidence generated over the last decade suggest that RT-induced cell death can also alter the tumor microenvironment (TME) and trigger an anti-tumor inflammatory response. [3][4][5][6] In light of recent clinical successes with immune checkpoint blockade (ICB)-mediated immune modulation in breast cancer together with a growing body of preclinical and clinical data demonstrating synergy between ICB and RT, [7][8][9] the clinical application of ICB with RT is an active area of investigation. Herein, we review the preclinical and clinical rationale for combining RT and ICB in breast cancer, early data from recent clinical trials, and relevant future directions.…”

Section: Introductionmentioning

confidence: 99%

Invasive Breast Carcinoma Tumor Size on Core Needle Biopsy: Analysis of Practice Patterns and Effect on Final Pathologic Tumor Stage

Agosto‐Arroyo

Tahmasbi

Diffalha

et al. 2018

Clinical Breast Cancer

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“…58,59 Furthermore, RT promotes the function and differentiation of cytotoxic T cells by inducing interleukin-1B, tumour necrosis factor-α, and interleukin-6. 13 Considering vasculature, low dose RT increases the ratio of antitumoural macrophages type 1 and tumour-promoting macrophages type 2, which leads to vascular normalisation and T cell recruitment. 60 Besides, low dose RT also appears to decrease TME's immunosuppressive cells such as Tregs and MDSCs.…”

Section: Role Of Anti-pd-1 and Radiotherapy In Immune Rejection Of Hnsccmentioning

confidence: 99%

“…75 Besides, RT increases tumour growth factor beta concentration which was shown to promote tumour-promoting macrophages type 2 differentiation and inhibit DCs and cytotoxic T cells. 13 In addition, RT was shown to even upregulate hypoxia inducible factor-1α, leading to eventual Treg and MDSC accumulation and DC and T cell inhibition via vascular endothelial growth factor. [76][77][78][79][80]…”

Section: Role Of Anti-pd-1 and Radiotherapy In Immune Rejection Of Hnsccmentioning

confidence: 99%

“…[10][11][12] Besides a well-known immunosuppressive effect of radiotherapy (RT), it can also lead to positive alterations in innate and adaptive immunity. 13 The same is true for the positive effects of the immune system on radiation efficacy, as a tumoricidal effect of RT is dependent on functional T cells, even at ablative doses. 14 Furthermore, RT induces programmed death-ligand 1 (PD-L1) expression in dendritic cells (DCs) and cancer cells which contributes to acquired cancer radioresistance, which could be overcome by concurrent anti-PD-1/L1.…”

Section: Introductionmentioning

confidence: 97%

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Combining radiotherapy and immunotherapy in definitive treatment of head and neck squamous cell carcinoma: review of current clinical trials

Plavc

Strojan

2020

Radiology and Oncology

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BackgroundHead and neck squamous cell carcinoma (HNSCC) presents as locally advanced disease in a majority of patients and is prone to relapse despite aggressive treatment. Since immune checkpoint inhibitors (ICI) have shown clinically significant efficacy in patients with recurrent/metastatic HNSCC (R/M HNSCC), a plethora of trials are investigating their role in earlier stages of disease. At the same time, preclinical data showed the synergistic role of concurrently administered radiotherapy and ICIs (immunoradiotherapy) and explained several mechanisms behind it. Therefore, this approach is prospectively tested in a neoadjuvant, definitive, or adjuvant setting in non-R/M HNSCC patients. Due to the intricate relationship between host, immunotherapy, chemotherapy, and radiotherapy, each of these approaches has its advantages and disadvantages. In this narrative review we present the biological background of immunoradiotherapy, as well as a rationale for, and possible flaws of, each treatment approach, and provide readers with a critical summary of completed and ongoing trials.ConclusionsWhile immunotherapy with ICIs has already become a standard part of treatment in patients with R/M HNSCC, its efficacy in a non-R/M HNSCC setting is still the subject of extensive clinical testing. Irradiation can overcome some of the cancer’s immune evasive manoeuvres and can lead to a synergistic effect with ICIs, with possible additional benefits of concurrent platinum-based chemotherapy. However, the efficacy of this combination is not robust and details in trial design and treatment delivery seem to be of unprecedented importance.

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Effects of Radiation on the Tumor Microenvironment

Cited by 43 publications

References 165 publications

Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose?

Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose?

Invasive Breast Carcinoma Tumor Size on Core Needle Biopsy: Analysis of Practice Patterns and Effect on Final Pathologic Tumor Stage

Combining radiotherapy and immunotherapy in definitive treatment of head and neck squamous cell carcinoma: review of current clinical trials

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