Rebalancing TGF-ß/PGE2 breaks RT-induced immunosuppressive barriers by enhancing tumor-infiltrated dendritic cell homing.

A better understanding of how tumor microenvironments shape immune responses after radiotherapy (RT) is required to improve patient outcomes. This study focuses on the observation that dendritic cells (DCs) infiltrating irradiated cervical tumors are retained in transforming growth factor (TGF)-ß-abundant regions. We report that TGF-ß secretion from cervical cancer cells was increased by irradiation in a dose-dependent manner and that this significantly suppressed the expression of allostimulatory markers and Th1 cytokines in DCs. To investigate further, we blocked the TGF-ß signal in DCs and observed that RT had a dose-dependent immune-promoting effect, improving DC maturation. This suggested that proinflammatory mediators may also be induced by RT, but their effects were being counteracted by the simultaneously increased levels of TGF-ß. Prostaglandin E2 (PGE2), a proinflammatory molecule, was shown to be one such mediator. Adjusting the TGF-ß/PGE2 ratio by inhibiting TGF-ß rebooted RT-induced DC cytoskeletal organization by stimulating myosin light chain (MLC) phosphorylation. Consequently, the homing of intra-tumorally infiltrated DCs to tumor-draining lymph nodes was enhanced, leading to the induction of more robust cytotoxic T cells. Ultimately, rebalancing the TGF-ß/PGE2 ratio amplified the therapeutic effects of RT, resulting in increased intra-tumoral infiltration and activation of CD8+ T cells, and improved tumor control and overall survival rate in mice. DC depletion experiments verified that the improvement in tumor control is directly correlated with the involvement of DCs via the PGE2-MLC pathway. This study emphasizes the importance of maintaining a balanced cytokine environment during RT, particularly hypofractionated RT; and it is advisable to block TGF-ß while preserving PGE2 in the tumor microenvironment in order to better stimulate DC homing and DC -T priming.

Daily Online Adaptive Radiation Therapy of Postoperative Endometrial and Cervical Cancer With PTV Margin Reduction to 5 mm: Dosimetric Outcomes, Acute Toxicity, and First Clinical Experience.

Purpose: This study evaluated the first clinical implementation of daily iterative cone beam computed tomography (iCBCT)-guided online adaptive radiation therapy (oART) in the postoperative treatment of endometrial and cervical cancer. Methods and Materials: Seventeen consecutive patients treated with daily iCBCT-guided oART were enrolled in this prospective study, with a reduced uniform 3-dimensional PTV margin of 5 mm. Treatment plans were designed to deliver 45 or 50.4 Gy in 1.8 Gy daily fractions to PTV. Pre- and posttreatment ultrasound and iCBCT scans were performed to record intrafractional bladder and rectal volume changes. The accuracy of contouring, oART procedure time, dosimetric outcomes, and acute toxicity were evaluated. Results: The average time from first iCBCT acquisition to completion of treatment was 22 minutes and 26 seconds. During this period, bladder volume increased by 44 cm3 using iCBCT contouring, whereas rectal volume remained stable (62.9 cm3 pretreatment vs 61.9 cm3 posttreatment). A total of 91.6% of influencers and 88.1% of CTVs required no or minor edits. The adapted plan was selected in all (434) fractions and significantly improved the dosimetry coverage for CTV and PTV, especially the vaginal PTV coverage by nearly 7% (P < .05). The adapted bladder Dmean was 104.61 cGy, and the rectum Dmean was 123.67 cGy, significantly lower than the scheduled plan of 108.24 and 128.19 cGy, respectively. The bone marrow and femur head left and right dosimetry were also improved with adaptation. Grade 2 acute gastrointestinal and genitourinary toxicities were 24% and 0, respectively. There was a grade 3 acute toxicity of decreased white blood cell count in 1 patient. Conclusions: Daily oART was associated with favorable dosimetry improvement and low acute toxicity, supporting its safety and efficacy for postoperative treatment of endometrial and cervical cancer. These results need to be validated in a larger prospective randomized controlled cohort.

Prospects for daily online adaptive radiotherapy for cervical cancer: Auto-contouring evaluation and dosimetric outcomes.

BACKGROUND: Training senior radiation therapists as "adapters" to manage influencers and target editing is critical in daily online adaptive radiotherapy (oART) for cervical cancer. The purpose of this study was to evaluate the accuracy and dosimetric outcomes of automatic contouring and identify the key areas for modification. METHODS: A total of 125 oART fractions from five postoperative cervical cancer patients and 140 oART fractions from five uterine cervical cancer patients treated with daily iCBCT-guided oART were enrolled in this prospective study. The same adaptive treatments were replanned using the Ethos automatic contours workflow without manual contouring edits. The clinical target volume (CTV) was subdivided into several separate regions, and the average surface distance dice (ASD), centroid deviation, dice similarity coefficient (DSC), and 95% Hausdorff distance (95% HD) were used to evaluate contouring for the above portions. Dosimetric results from automatic oART plans were compared to supervised oART plans to evaluate target volumes and organs at risk (OARs) dose changes. RESULTS: Overall, the paired CTV had high overlap rates, with an average DSC value greater than 0.75. The uterus had the largest consistency differences, with ASD, centroid deviation, and 95% HD being 2.67 ± 1.79 mm, 17.17 ± 12 mm, and 10.45 ± 5.68 mm, respectively. The consistency differences of the lower nodal CTVleft and nodal CTVright were relatively large, with ASD, centroid deviation, and 95% HD being 0.59 ± 0.53 mm, 3.6 ± 2.67 mm, and 5.41 ± 4.08 mm, and 0.59 ± 0.51 mm, 3.6 ± 2.54 mm, and 4.7 ± 1.57 mm, respectively. The automatic online-adapted plan met the clinical requirements of dosimetric coverage for the target volume and improved the OAR dosimetry. CONCLUSIONS: The accuracy of automatic contouring from the Ethos adaptive platform is considered clinically acceptable for cervical cancer, and the uterus, upper vaginal cuff, and lower nodal CTV are the areas that need to be focused on in training.