Dharmapuri Sirish, Cabal Rafael, Akturk Guray, Ioannou Giorgio, Ozbey Sinem, Paulsen John, Raina Sheen, Ang Celina, Sarpel Umut, Sung Max W, Kozuch Peter, Schwartz Myron E, Cohen Deirdre Jill, Gnjatic Sacha, Pintova Sofya
Division of Medical Oncology, Department of Hematology and Oncology, Icahn School of Medicine at Mount Sinai West, Tisch Cancer Institute, New York, NY, USA.
Division of Molecular and Cell-Based Medicine, Department of Pathology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA.
Ann Transl Med. 2024 Aug 1;12(4):78. doi: 10.21037/atm-23-1928. Epub 2024 Jun 5.
Neoadjuvant chemotherapy (NACT) is increasingly being used in the management of locally advanced biliary tract cancer (BTC). The evidence suggests a contributing role of tumor infiltrating immune cells in the prognosis and response. We set out to characterize immune modulation of tumor immune microenvironment in BTC following NACT.
Patients with BTC who underwent diagnostic biopsy, then NACT then resection between 2014-2018 were identified. Multiplexed immunohistochemical consecutive staining on single slide (MICSSS) analysis was performed with a series of immune markers to characterize T-cells, immune checkpoints etc. on pre- & post-NACT tumor tissue. Density was calculated for each marker. The final analysis included five patients. Median age was 48 (range, 41-56) years, with 4 female, 4 intrahepatic cholangiocarcinoma and 1 gallbladder. All patients received gemcitabine/cisplatin as NACT (median of 5 cycles). Median time from diagnosis to surgery was 4.3 (range, 1.4-7.8) months. All patients were mismatch repair proficient (pMMR). NACT on average produced a depletion of all immune markers. Given small sample size, each patient was considered their own control and changes in mean cell densities post-NACT were calculated. Patient #2 with a 40-fold increase in PD-L1 expression & 5-fold decrease in CD8:FOXP3 ratio after NACT notably had the shortest disease-free interval (DFI). Patient #3 with the longest DFI had the largest increase in CD8:FOXP3 by about 8-fold with a decrease in PD-L1.
Preliminary results suggest NACT may differentially modulate various compartments of the immune tumor contexture despite overall cell depletion. Future studies should focus on strategies to expand immune modulation of tumor microenvironment, including immune-oncology agents to augment the effects of chemotherapy.
新辅助化疗（NACT）越来越多地用于局部晚期胆管癌（BTC）的治疗。有证据表明肿瘤浸润免疫细胞在预后和反应中起作用。我们着手对NACT后BTC中肿瘤免疫微环境的免疫调节进行特征分析。
确定了2014年至2018年间接受诊断性活检、然后NACT、然后手术切除的BTC患者。使用一系列免疫标志物对单张载玻片进行多重免疫组织化学连续染色（MICSSS）分析，以表征NACT前后肿瘤组织中的T细胞、免疫检查点等。计算每个标志物的密度。最终分析纳入了5名患者。中位年龄为48岁（范围41 - 56岁），其中4名女性，4例肝内胆管癌和1例胆囊癌。所有患者均接受吉西他滨/顺铂作为NACT（中位5个周期）。从诊断到手术的中位时间为4.3个月（范围1.4 - 7.8个月）。所有患者错配修复功能正常（pMMR）。NACT平均导致所有免疫标志物减少。鉴于样本量小，将每位患者视为自身对照，并计算NACT后平均细胞密度的变化。患者2在NACT后PD-L1表达增加40倍，CD8:FOXP3比值降低5倍，其无病生存期（DFI）明显最短。无病生存期最长的患者3的CD8:FOXP3增加幅度最大，约为8倍，而PD-L1减少。
初步结果表明，尽管总体细胞减少，但NACT可能对免疫肿瘤结构的各个部分进行不同的调节。未来的研究应集中在扩大肿瘤微环境免疫调节的策略上，包括免疫肿瘤药物以增强化疗效果。
