The paradox of radiation and T cells in tumors

Gough, Michael; Crittenden, Marka R.

doi:10.1016/j.neo.2022.100808

Cited by 24 publications

(13 citation statements)

References 183 publications

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“…For example, in a model where high-dose RT (30 Gy) resulted in effective CD8 + T-cells anti-tumor response, adding fractionated RT (3 Gy ×10) decreased tumor control ( 51 ). These data demonstrate that extending the timeline of radiation treatment can kill T-cells which are critical for tumor control ( 52 ).…”

Section: The Immunogenic Radiationmentioning

confidence: 80%

“…The clearest data relating to the impact of radiation on the immune profile of tumors is the direct radiation-mediated killing of T-cells in the treatment field [reviewed in ( 52 )]. Systemic lymphocyte loss is another immune-related outcome observed in patients treated with conventionally fractionated radiation ( Figure 1 ) ( 11 , 12 , 70 – 75 ), though alterations in dose and fractionation can limit this effect ( 76 , 77 ).…”

Section: The Immunogenic Radiationmentioning

confidence: 99%

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The immunogenic radiation and new players in immunotherapy and targeted therapy for head and neck cancer

Sharon,

Daher-Ghanem,

Zaid

et al. 2023

Front. Oral. Health

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Although treatment modalities for head and neck cancer have evolved considerably over the past decades, survival rates have plateaued. The treatment options remained limited to definitive surgery, surgery followed by fractionated radiotherapy with optional chemotherapy, and a definitive combination of fractionated radiotherapy and chemotherapy. Lately, immunotherapy has been introduced as the fourth modality of treatment, mainly administered as a single checkpoint inhibitor for recurrent or metastatic disease. While other regimens and combinations of immunotherapy and targeted therapy are being tested in clinical trials, adapting the appropriate regimens to patients and predicting their outcomes have yet to reach the clinical setting. Radiotherapy is mainly regarded as a means to target cancer cells while minimizing the unwanted peripheral effect. Radiotherapy regimens and fractionation are designed to serve this purpose, while the systemic effect of radiation on the immune response is rarely considered a factor while designing treatment. To bridge this gap, this review will highlight the effect of radiotherapy on the tumor microenvironment locally, and the immune response systemically. We will review the methodology to identify potential targets for therapy in the tumor microenvironment and the scientific basis for combining targeted therapy and radiotherapy. We will describe a current experience in preclinical models to test these combinations and propose how challenges in this realm may be faced. We will review new players in targeted therapy and their utilization to drive immunogenic response against head and neck cancer. We will outline the factors contributing to head and neck cancer heterogeneity and their effect on the response to radiotherapy. We will review in-silico methods to decipher intertumoral and intratumoral heterogeneity and how these algorithms can predict treatment outcomes. We propose that (a) the sequence of surgery, radiotherapy, chemotherapy, and targeted therapy should be designed not only to annul cancer directly, but to prime the immune response. (b) Fractionation of radiotherapy and the extent of the irradiated field should facilitate systemic immunity to develop. (c) New players in targeted therapy should be evaluated in translational studies toward clinical trials. (d) Head and neck cancer treatment should be personalized according to patients and tumor-specific factors.

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Section: The Immunogenic Radiationmentioning

confidence: 80%

Section: The Immunogenic Radiationmentioning

confidence: 99%

The immunogenic radiation and new players in immunotherapy and targeted therapy for head and neck cancer

Sharon,

Daher-Ghanem,

Zaid

et al. 2023

Front. Oral. Health

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“…However, accurate estimation of the radiation dose delivered to lymphocytes is a complex task considering lymphocytes' recirculation and homing process, mediated by specific biological mechanism such as L-selectin (or CD62L) receptor and Sphingosine-1-Phosphate (S1P) pathways. Lymphocytes can traffic along lymph vessels and through lymphoid organs, thus transiently exit the blood circulation and reintegrate it later, implying that the whole blood-circulating lymphocyte pool can be renewed up to 11 times a day (GOWANS 1957, Gough andCrittenden 2022). Thus, peripheral lymphocytes present in the blood at the time of irradiation can be different from a radiation fraction to another, and models restricted to circulating lymphocytes may significantly misestimate the lymphocyte dose.…”

Section: Discussionmentioning

confidence: 99%

LymphoDose: a lymphocyte dose estimation framework—application to brain radiotherapy

de Kermenguy,

Benzazon,

Maury

et al. 2024

Phys. Med. Biol.

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Objective: Severe radiation-induced lymphopenia occurs in 40% of patients treated for primary brain tumors and is an independent risk factor of poor survival outcomes. We developed an in-silico framework that estimates the radiation doses received by lymphocytes during VMAT brain irradiation. Approach: We implemented a simulation consisting of two interconnected compartmental models describing the slow recirculation of lymphocytes between lymphoid organs (M_1) and the bloodstream (M_2). We used dosimetry data from 33 patients treated with chemo-radiation for glioblastoma to compare three cases of the model, corresponding to different physical and biological scenarios: H1) lymphocytes circulation only in the bloodstream i.e., circulation in M_2 only; H2) lymphocytes recirculation between lymphoid organs i.e. circulation in M_1 and M_2 interconnected; H3) lymphocytes recirculation between lymphoid organs and deep-leaning computed out-of-field dose to head and neck lymphoid structures. A sensitivity analysis of the model's parameters was also performed. Main results: For H1, H2 and H3 cases respectively, the irradiated fraction of lymphocytes was 99.8±0.7%, 40.4±10.2% et 97.6±2.5%, and the average dose to irradiated pool was 309.9±74.7mGy, 52.6±21.1mGy and 265.6±48.5mGy. The recirculation process considered in the H2 case implied that irradiated lymphocytes were irradiated in the field only 1.58±0.91 times on average after treatment. The out-of-field irradiation of head and neck lymphoid structures considered in H3 was an important contribution to lymphocytes dose. In all cases, the estimated doses are low compared with lymphocytes radiosensitivity, and other mechanisms could explain high prevalence of RIL in patients with brain tumors.Significance: Our framework is the first to take into account out-of-field doses and recirculation in lymphocyte dose assessment during brain irradiation. Our results demonstrate the need to clarify the indirect effects of irradiation on lymphopenia, in order to potentiate the combination of radio-immunotherapy or the abscopal effect.

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“…Existing data do not indicate an important role for CD4 + T cells in response to IR in most murine tumor models, with the exception of a few studies testing combinations: IR + all-trans retinoic acid, where CD4 + T cells were required for the manifestation of full anti-tumor effects ( Rao et al, 2021 ); IR + vaccination of CD4 + antigen, where CD4 + T cells are posited to be important for sustained CD8 + T cell activation ( Lhuillier et al, 2021 ); and combination IR + monophosphoryl lipid A treatment, which generates a systemic anti-tumor immune response in a Th1-CD4 + T cell–dependent manner in murine melanoma and prostate cancer models ( Jagodinsky et al, 2022 ). Although IR alone activates T cells, they are often quickly exhausted or limited by TME-expressing immune checkpoints induced by IR, such as PD-L1 and CTLA-4 ( Gough and Crittenden, 2022 ).…”

Section: Preclinical Studies Of Radiation and Anti-tumor Immunitymentioning

confidence: 99%

Radiotherapy and immunology

Wang,

Lynch,

Pitroda

et al. 2024

Journal of Experimental Medicine

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The majority of cancer patients receive radiotherapy during the course of treatment, delivered with curative intent for local tumor control or as part of a multimodality regimen aimed at eliminating distant metastasis. A major focus of research has been DNA damage; however, in the past two decades, emphasis has shifted to the important role the immune system plays in radiotherapy-induced anti-tumor effects. Radiotherapy reprograms the tumor microenvironment, triggering DNA and RNA sensing cascades that activate innate immunity and ultimately enhance adaptive immunity. In opposition, radiotherapy also induces suppression of anti-tumor immunity, including recruitment of regulatory T cells, myeloid-derived suppressor cells, and suppressive macrophages. The balance of pro- and anti-tumor immunity is regulated in part by radiotherapy-induced chemokines and cytokines. Microbiota can also influence radiotherapy outcomes and is under clinical investigation. Blockade of the PD-1/PD-L1 axis and CTLA-4 has been extensively investigated in combination with radiotherapy; we include a review of clinical trials involving inhibition of these immune checkpoints and radiotherapy.

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The paradox of radiation and T cells in tumors

Cited by 24 publications

References 183 publications

The immunogenic radiation and new players in immunotherapy and targeted therapy for head and neck cancer

The immunogenic radiation and new players in immunotherapy and targeted therapy for head and neck cancer

LymphoDose: a lymphocyte dose estimation framework—application to brain radiotherapy

Radiotherapy and immunology

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