Upfront dose-reduced chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma

• DOI: 10.1136/jitc-2020-000807
• Publication Date: 2020-10-28T21:10:30Z
• Authors: Xiran He; Yang Du; Zhijie Wang; Xin Wang; Jianchun Duan; Rui Wan; Jiachen Xu; Pei Zhang; Di Wang; Yanhua Tian; Jiefei Han; Kailun Fei; Hua Bai; Jie Tian; Jie Wang
• Keywords: Chemoimmunotherapy

Background The survival benefits of combining chemotherapy (at the maximum tolerated dose, MTD) with concurrent immunotherapy, collectively referred to as chemoimmunotherapy, for treatment squamous cell lung carcinoma (SQCLC) have been confirmed in recent clinical trials. Nevertheless, optimization chemoimmunotherapy order enhance efficacy immune checkpoint inhibitors (ICIs) SQCLC remains be explored. Methods Cell lines, syngeneic immunocompetent mouse models, and patients’ peripheral blood mononuclear cells were used comprehensively explore how ectopic lymphoid-like structures (ELSs) upregulate therapeutic targets anti-programmed death 1 (PD-1)/anti-PD-1 ligand (PD-L1) monoclonal antibodies (mAbs), thus rendering more sensitive ICIs. In addition, molecular mechanisms underlying characterized. Results Low-dose contributed an enhanced antigen exposure via phosphatidylinositol 3-kinase/Akt/transcription factor nuclear kappa B signaling pathway. Improved uptake presentation by activated dendritic (DCs) was observed, invoking specific T responses leading systemic immunological memory. turn, antitumor ELSs PD-1/PD-L1 expression observed vivo. Moreover, upfront metronomic (low-dose frequent administration) extended time window immunostimulatory effect effectively synergized anti-PD-1/PD-L1 mAbs. A possible mechanism this synergy is increase type I macrophages, DCs, cytotoxic CD8 + cells, well maintenance intestinal gut microbiota diversity composition. contrast, when routine MTD ICIs, effects appeared additive rather than synergistic. Conclusions We first attempted optimize investigating different combinatorial modes. Compared current practice, performed better subsequent mAb treatment. This combination approach worth other types tumors, followed translation into clinic future.