Eric Lambaudie

Tertiary Lymphoid Structures Are Associated with Enhanced Macrophage Activation and Immune Checkpoint Expression and Predict Outcome in Cervical Cancer

Abstract Cervical tumors are usually treated using surgery, chemotherapy, and radiotherapy and would benefit from immunotherapies. However, the immune microenvironment in cervical cancer remains poorly described. Tertiary lymphoid structures (TLS) were recently described as markers for better immunotherapy response and overall better prognosis in patients with cancer. We evaluated the cervical tumor immune microenvironment, specifically focusing on TLS, using combined high-throughput phenotyping, soluble factor concentration dosage in the tumor microenvironment, and spatial interaction analyses. We found that TLS presence was associated with a more inflammatory soluble microenvironment, with the presence of B cells as well as more activated macrophages and dendritic cells (DC). Furthermore, this myeloid cell activation was associated with the expression of immune checkpoints, such as PD-L1 and CD40, and the proximity of activated conventional type 2 DCs to CD8+ T cells, indicating better immune interactions and tumor control. Finally, we associated TLS presence, greater B-cell density, and activated DC density with improved progression-free survival, substantiating TLS presence as a potential prognostic marker. Our results provide evidence that TLS presence denotes cell activation and immunotherapy target expression.

The influence of time and implants in high-dose rate image-guided adaptive brachytherapy for locally advanced cervical cancer

To compare the clinical outcomes of two different schedules of modern image-guided adaptive brachytherapy (IGABT) in patients underwent chemoradiotherapy (CCRT) and high-dose rate (HDR) brachytherapy (BT) for locally advanced cervical cancer treated (LACC) METHODS AND MATERIALS: Data from medical records of all consecutive patients with histologically proven cervical cancer (FIGO 2018 stage IB-IVA) treated by HDR-BT after CCRT at our institution between 2016 and 2021 were reviewed. Two hundred and 8 patients with LACC FIGO 2018 stages (IB 20.7%; II 26.5%, III 51%, IVA 1.9%) underwent brachytherapy at our institution. Depending on initial clinical features of disease and the clinical response to CCRT, HDR-BT was delivered with one implant (BT1i) or two implants (BT2i) in 39% and 61% of patients respectively. FIGO stages (≥IIB) were 63% vs. 78% for BT1i and BT2i patient group respectively. Combined brachytherapy technique [endocavitary/interstitial (IC/IS)] was required in 14.8% vs. 68.5% for BT1i and BT2i respectively. With a median follow-up of 32.5 months (95% confidence interval, [29.7-35.8]), local relapse was observed in sixteen patients: 8 patients (3.8%) had local (exclusive) relapse and 8 patients (3.8%) had locally persistent and progressive disease, without significant difference for each BT modality group (p = 0.27), even if BT2i group had more aggressive initial disease. The estimated 3-year disease free survival and overall survival for the entire population was 69% (95% confidence interval, [62-75%]) and 88% (95% confidence interval, [82-92%]) respectively. There was a significant difference in the incidence of global toxicity grade G≥2 in favour to the BT2i group (p = 0.026). HDR brachytherapy delivered with a long time interval between fractions, two implants, and combined IC/IS brachytherapy is the best way to ensure local control and to perform IGABT with low toxicity, even in advanced stages of disease.