Fractionated Radiation Severely Reduces the Number of CD8+ T Cells and Mature Antigen Presenting Cells Within Lung Tumors

Reijmen, Eva; Mey, Sven de; Mey, Wout de; Gevaert, Thierry; Ridder, Kirsten De; Locy, Hanne; Martens, Sandrina; Blay, Emmy De; Bouwens, Luc; Debie, Pieterjan; Breckpot, Karine; Grève, Jacques De; Ridder, Mark De; Goyvaerts, Cleo

doi:10.1016/j.ijrobp.2021.04.009

Cited by 24 publications

(19 citation statements)

References 49 publications

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“…Reijmen et al evaluated the therapeutic and immunologic effects of low-dose fractionated RT on lung cancers in mice. They found that 4 consecutive daily fractions of RT at 3.2 Gy severely reduced the number of CD8 + T cells and mature antigen presenting cells within lung tumors [73]. Therefore, the ideal use of radiation as an immune stimulator may be induction of immunogenic cell death of tumor cells while avoiding radiation to the TDLN to preserve populations of CD8 + T cells and mature antigen presenting cells.…”

Section: Pre-clinical Datamentioning

confidence: 99%

The Abscopal Effect: A Review of Pre-Clinical and Clinical Advances

Janopaul‐Naylor

Shen

Qian

et al. 2021

IJMS

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Radiotherapy has been used for more than a hundred years to cure or locally control tumors. Regression of tumors outside of the irradiated field was occasionally observed and is known as the abscopal effect. However, the occurrence of systemic anti-tumor effects was deemed too rare and unpredictable to be a therapeutic goal. Recent studies suggest that immunotherapy and radiation in combination may enhance the abscopal response. Increasing numbers of cases are being reported since the routine implementation of immune checkpoint inhibitors, showing that combined radiotherapy with immunotherapy has a synergistic effect on both local and distant (i.e., unirradiated) tumors. In this review, we summarize pre-clinical and clinical reports, with a specific focus on the mechanisms behind the immunostimulatory effects of radiation and how this is enhanced by immunotherapy.

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Section: Pre-clinical Datamentioning

confidence: 99%

The Abscopal Effect: A Review of Pre-Clinical and Clinical Advances

Janopaul‐Naylor

Shen

Qian

et al. 2021

IJMS

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“…While tumor irradiation can activate anti-tumor immunity through the induction of immunogenic cell death, the latter can also be counteracted by the accumulation of radioresistant immunosuppressive cells, including TAMs, MDSCs and Tregs ( 20 , 21 ). We previously confirmed that systemic and especially local immunosuppression predominates in a murine orthotopic NSCLC model when treated with clinically relevant, low-dose fractionated RT ( 22 ). In addition to reduced numbers of CTLs and mature CD86 + DCs, the fractions of TAMs, Tregs, monocytes and neutrophils increased upon RT treatment.…”

Section: Introductionmentioning

confidence: 61%

“…Using a similar experimental setup and lung tumor model as depicted in Figure 1A , we previously observed that fractionated RT results in significant reduction of lung tumor growth ( 22 ). However, we and others showed that fractionated RT results in a reduction of the tumor infiltrated CD8 + CTL fraction, while the abundance of immunosuppressive myeloid cells increased.…”

Section: Resultsmentioning

confidence: 92%

“…Lewis lung carcinoma, positive for Firefly luciferase (LLC-Fluc), were previously generated using a Fluc-encoding lentiviral vector (transfer plasmid pDUAL_SFFV-Fluc_Ub-puroR) as described ( 22 , 49 ). Cells were maintained in Dulbecco’s Modified Eagle’s Medium (DMEM, Sigma-Aldrich) supplemented with 10% fetal bovine serum (FBS, Harlan), 100 units/ml penicillin, 100 µg/ml streptomycin and 2 mM L-Glutamine (Sigma-Aldrich) at 37°C, 5% CO 2 , 21% O 2 and humidity level of 95%.…”

Section: Methodsmentioning

confidence: 99%

“…One week after LLC-Fluc injection, in vivo bioluminescence imaging (BLI) was used to visualize tumor burden ( 50 ) and randomize mice with similar photon counts to one of four different treatment groups: VNS only, RT+sham, RT+VNS or sham (control). Radiation treatment was performed from day 11 in 4 consecutive daily fractions of 3,2 Gy as previously described ( 22 ). In brief, Ketamine (Ketamidor ® , UK, 100mg kg -1 )/Xylazine (Rompun ® , Germany, 10 mg kg -1 ) anesthetized mice were positioned in a 3D-printed mold (Ultimaker Extended 2+ using PLA filaments) and irradiated with the indicated doses using the Truebeam STx system (Varian, Palo Alto, CA, USA; BrainLAB AG, Feldkirchen, Germany).…”

Section: Methodsmentioning

confidence: 99%

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Transcutaneous Vagal Nerve Stimulation Alone or in Combination With Radiotherapy Stimulates Lung Tumor Infiltrating Lymphocytes But Fails to Suppress Tumor Growth

et al. 2021

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The combination of radiotherapy (RT) with immunotherapy represents a promising treatment modality for non-small cell lung cancer (NSCLC) patients. As only a minority of patients shows a persistent response today, a spacious optimization window remains to be explored. Previously we showed that fractionated RT can induce a local immunosuppressive profile. Based on the evolving concept of an immunomodulatory role for vagal nerve stimulation (VNS), we tested its therapeutic and immunological effects alone and in combination with fractionated RT in a preclinical-translational study. Lewis lung carcinoma-bearing C57Bl/6 mice were treated with VNS, fractionated RT or the combination while a patient cohort with locally advanced NSCLC receiving concurrent radiochemotherapy (ccRTCT) was enrolled in a clinical trial to receive either sham or effective VNS daily during their 6 weeks of ccRTCT treatment. Preclinically, VNS alone or with RT showed no therapeutic effect yet VNS alone significantly enhanced the activation profile of intratumoral CD8+ T cells by upregulating their IFN-γ and CD137 expression. In the periphery, VNS reduced the RT-mediated rise of splenic, but not blood-derived, regulatory T cells (Treg) and monocytes. In accordance, the serological levels of protumoral CXCL5 next to two Treg-attracting chemokines CCL1 and CCL22 were reduced upon VNS monotherapy. In line with our preclinical findings on the lack of immunological changes in blood circulating immune cells upon VNS, immune monitoring of the peripheral blood of VNS treated NSCLC patients (n=7) did not show any significant changes compared to ccRTCT alone. As our preclinical data do suggest that VNS intensifies the stimulatory profile of the tumor infiltrated CD8+ T cells, this favors further research into non-invasive VNS to optimize current response rates to RT-immunotherapy in lung cancer patients.

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A randomized phase II clinical trial of stereotactic body radiation therapy (SBRT) and systemic pembrolizumab with or without intratumoral avelumab/ipilimumab plus CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells in solid tumors

Vounckx,

Tijtgat,

Stevens

et al. 2024

Cancer Immunol Immunother

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Background Radiotherapy (RT) synergizes with immune checkpoint blockade (ICB). CD1c(BDCA-1)+/CD141(BDCA-3)+ myeloid dendritic cells (myDC) in the tumor microenvironment are indispensable at initiating effector T-cell responses and response to ICB. Methods In this phase II clinical trial, anti-PD-1 ICB pretreated oligometastatic patients (tumor agnostic) underwent a leukapheresis followed by isolation of CD1c(BDCA-1)+/CD141(BDCA-3)+ myDC. Following hypofractionated stereotactic body RT (3 × 8 Gy), patients were randomized (3:1). Respectively, in arm A (immediate treatment), intratumoral (IT) ipilimumab (10 mg) and avelumab (40 mg) combined with intravenous (IV) pembrolizumab (200 mg) were administered followed by IT injection of myDC; subsequently, IV pembrolizumab and IT ipilimumab/avelumab were continued (q3W). In arm B (contemporary control arm), patients received IV pembrolizumab, with possibility to cross-over at progression. Primary endpoint was 1-year progression-free survival rate (PFS). Secondary endpoints were safety, feasibility, objective response rate, PFS, and overall survival (OS). Results Thirteen patients (10 in arm A, eight non-small cell lung cancer, and five melanoma) were enrolled. Two patients crossed over. One-year PFS rate was 10% in arm A and 0% in arm B. Two patients in arm A obtained a partial response, and one patient obtained a stable disease as best response. In arm B, one patient obtained a SD. Median PFS and OS were 21.8 weeks (arm A) versus 24.9 (arm B), and 62.7 versus 57.9 weeks, respectively. An iatrogenic pneumothorax was the only grade 3 treatment-related adverse event. Conclusion SBRT and pembrolizumab with or without IT avelumab/ipilimumab and IT myDC in oligometastatic patients are safe and feasible with a clinically meaningful tumor response rate. However, the study failed to reach its primary endpoint. Trial registration number: Clinicaltrials.gov: NCT04571632 (09 AUG 2020). EUDRACT: 2019-003668-32. Date of registration: 17 DEC 2019, amendment 1: 6 MAR 2021, amendment 2: 4 FEB 2022.

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Fractionated Radiation Severely Reduces the Number of CD8+ T Cells and Mature Antigen Presenting Cells Within Lung Tumors

Cited by 24 publications

References 49 publications

The Abscopal Effect: A Review of Pre-Clinical and Clinical Advances

The Abscopal Effect: A Review of Pre-Clinical and Clinical Advances

Transcutaneous Vagal Nerve Stimulation Alone or in Combination With Radiotherapy Stimulates Lung Tumor Infiltrating Lymphocytes But Fails to Suppress Tumor Growth

A randomized phase II clinical trial of stereotactic body radiation therapy (SBRT) and systemic pembrolizumab with or without intratumoral avelumab/ipilimumab plus CD1c (BDCA-1)+/CD141 (BDCA-3)+ myeloid dendritic cells in solid tumors

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