The mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an open conundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefits of immune checkpoint inhibitors or chemotherapy in eight retrospective cohorts of cancer patients and in tumor-bearing mice. The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and on the metabolic and immune host-microbiota interaction at baseline allowing CD8⁺ T cell activation without exhaustion. Various strains of Christensenella minuta selectively boost the anti-cancer efficacy of ILDR and PD-L1 blockade, allowing emigration of intestinal PD-L1-expressing dendritic cells to tumor-draining lymph nodes. An interventional phase 2 study provides the proof-of-concept that ILDR can circumvent resistance to first- or second-line immunotherapy in cancer patients. Prospective clinical trials are warranted to define optimal dosimetry and indications for ILDR to maximize its therapeutic potential.

Purpose: We aimed to develop a combined predicting model for benign esophageal stenosis (BES) after simultaneous integrated boost (SIB) with concurrent chemotherapy in patients with esophageal squamous cell carcinoma (ESCC).Methods: This study included 65 patients with EC who underwent SIB with chemotherapy. Esophageal stenosis was evaluated using esophagograms and the severity of eating disorders. Risk factors were investigated using univariate and multivariate analyses. Radiomics features were extracted based on contrast-enhanced CT (CE-CT) before treatment. The least absolute shrinkage and selection operator (LASSO) regression analysis was used for feature selection and radiomics signature construction. The model’s performance was evaluated using Harrell’s concordance index and receiver operating characteristic curves.Results: The patients were stratified into low- and high-risk groups according to BES after SIB. The area under the curves of the clinical model, Rad-score, and the combined model were 0.751, 0.820 and 0.864, respectively. In the validation cohort, the AUCs of these three models were 0.854, 0.883 and 0.917, respectively. The Hosmer-Lemeshow test showed that there was no deviation from model fitting for the training cohort (p=0.451) and validation cohort (p=0.481). The C-indexes of the nomogram were 0.864 and 0.958 for the training and validation cohort, respectively. The model combined with Rad-score and clinical factors achieved favorable prediction ability.Conclusion: Definitive chemoradiotherapy could alleviate tumor-inducing esophageal stenosis but result in benign stenosis. We constructed and tested a combined predicting model for benign esophageal stenosis after SIB. The nomogram incorporating both radiomics signature and clinical prognostic factors showed favorable predictive accuracy for BES in ESCC patients who received SIB with chemotherapy.Trial registration number and date of registration: Registered in www.Clinicaltrial.gov, ID: NCT01670409, August 12, 2012

The study aimed to appraise the dose differences between Acuros XB (AXB) and Anisotropic Analytical Algorithm (AAA) in stereotactic body radiotherapy (SBRT) treatment for lung cancer with flattening filter free (FFF) beams. Additionally, the potential role of the calculation grid size (CGS) on the dose differences between the two algorithms was also investigated. SBRT plans with 6X and 10X FFF beams produced from the CT scan data of 10 patients suffering from stage I lung cancer were enrolled in this study. Clinically acceptable treatment plans with AAA were recalculated using AXB with the same monitor units (MU) and identical multileaf collimator (MLC) settings. Furthermore, different CGS (2.5 mm and 1 mm) in the two algorithms was also employed to investigate their dosimetric impact. Dose to planning target volumes (PTV) and organs at risk (OARs) between the two algorithms were compared. PTV was separated into PTV_soft (density in soft-tissue range) and PTV_lung (density in lung range) for comparison. The dose to PTV_lung predicted by AXB was found to be 1.33 ± 1.12% (6XFFF beam with 2.5 mm CGS), 2.33 ± 1.37% (6XFFF beam with 1 mm CGS), 2.81 ± 2.33% (10XFFF beam with 2.5 mm CGS) and 3.34 ± 1.76% (10XFFF beam with 1 mm CGS) lower compared with that by AAA, respectively. However, the dose directed to PTV_soft was comparable. For OARs, AXB predicted a slightly lower dose to the aorta, chest wall, spinal cord and esophagus, regardless of whether the 6XFFF or 10XFFF beam was utilized. Exceptionally, dose to the ipsilateral lung was significantly higher with AXB. AXB principally predicts lower dose to PTV_lung compared to AAA and the CGS contributes to the relative dose difference between the two algorithms.

Radiation dose escalation by simultaneous modulated accelerated radiotherapy combined with chemotherapy for esophageal cancer: a phase II study

Esophageal squamous cell carcinoma (ESCC) is an aggressive and fatal disease that is usually diagnosed when the chances for surgical intervention has been missed. Definitive concurrent chemoradiotherapy (dCRT) is the first choice of treatment for inoperable locally advanced esophageal squamous cell carcinoma (LA-ESCC). Nevertheless, the local recurrence rate for esophageal cancer patients undergoing dCRT remains high at 40-60%, with a 5-year overall survival rate of solely 10-30%. Immunotherapy in combination with dCRT is a promising treatment for inoperable LA-ESCC, for that improved long-term survival is expected. The present review provides a comprehensive overview of the evolutionary trajectory of dCRT for LA-ESCC, delineates notable relevant clinical studies, addresses unresolved concerns regarding the combination of dCRT with immunotherapy, and highlights promising directions for future research. When dCRT is combined with immunotherapy, the following aspects should be carefully explored in the future studies, including the optimal irradiation dose, segmentation scheme, radiotherapy technique, timing, sequence and duration of radiotherapy, and the selection of chemotherapeutic and immunologic drugs. In addition, further investigations on the mechanisms of how dCRT combined with immunotherapy exerts synergistic anti-tumor effects and molecular biomarkers ensuring precise screening of ESCC patients are needed.

Purpose: To ask whether the expression of immune markers and IFN signaling in tumor biopsies changes during concurrent chemoradiotherapy (CCRT). Experimental Design: Tumor biopsies and peripheral mononuclear blood cells (PMBC) before and immediately after 20 Gy/10 fractions (F) of radiation treatment (RT) from 30 patients with cervical cancer receiving CCRT were evaluated by IHC and qRT-PCR for immune markers and correlated with the short-term response. Results: Tumor immune response to radiation before and after 10F RT as reflected by CD8+ T-cell infiltration had substantial heterogeneity with increases, decreases, and no change all evident. Increases in CD8+ T cells during CCRT correlated with the presence of nuclear IRF1 in tumor cells (r = 0.68, P < 0.0001) and the patient short-term response (P < 0.01). Similarly, in a subset of patients (∼40%) PD-L1 positivity in tumor cells increased, which also correlated with nuclear IRF1 staining (r = 0.48, P < 0.01). Patients with augmented PMBC IFN signature expression after 10F had a significantly higher probability of PD-L1 induction (83% vs. 7%, P < 0.0001). Most patients exhibited abundant expression of SERPINB9 and CD47 in tumor cells, and tumor infiltration by CD68+ cells. SERPINB9 expression correlated with STAT1 signaling in tumor cells. Conclusions: CCRT leads to differential tumor immunogenicity and IFN signaling in patients with cervical cancer, suggesting radiation induction of immunity is limited to a subset of patients and may reflect the heterogeneity of intratumoral induction of IFNs. See related commentary by Mondini and Deutsch, p. 3815