No abstract

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The expression of programmed death ligand-1 (PD-L1) is controlled by complex mechanisms. The elucidation of the molecular mechanisms of PD-L1 expression is important for the exploration of new insights into PD-1 blockade therapy. Detailed mechanisms of the in situ expression of PD-L1 in tissues of oral squamous cell carcinomas (OSCCs) have not yet been clarified. We examined the mechanisms of PD-L1 expression focusing on the phosphorylation of downstream molecules of epidermal growth factor (EGF) and interferon gamma (IFN-γ) signaling in vitro and in vivo by immunoblotting and multi-fluorescence immunohistochemistry (MF-IHC), respectively. The in vitro experiments demonstrated that PD-L1 expression in OSCC cell lines is upregulated by EGF via the EGF receptor (EGFR)/PI3K/AKT pathway, the EGFR/STAT1 pathway, and the EGFR/MEK/ERK pathway, and by IFN-γ via the JAK2/STAT1 pathway. MF-IHC demonstrated that STAT1 and EGFR phosphorylation was frequently shown in PD-L1-positive cases and STAT1 phosphorylation was correlated with lymphocyte infiltration and EGFR phosphorylation. Moreover, the phosphorylation pattern of the related molecules in PD-L1-positive cells differed among the cases investigated. These findings indicate that PD-L1 expression mechanisms differ depending on the tissue environment and suggest that the examination of the tissue environment and molecular alterations of cancer cells affecting PD-L1 expression make it necessary for each patient to choose the appropriate combination drugs for PD-1 blockade cancer treatment.

We studied subsets and cytotoxicity of recombinant interleukin-2 (rIL-2)-expanded tumor-infiltrating lymphocytes (TIL) from renal cell cancer (RCC) patients. TIL were successfully expanded in 13 of 14 RCC cases using anti-CD3 during the initial 48 h of culture. Percentages of CD8-positive cells among rIL-2-expanded TIL at 1–4 week(s) of culture were 56.2 ± 15.1% (range 26.2–79.8% n = 13) and not necessarily predominant over CD4-positive cells. Natural killer and lymphokine-activated killer (LAK) activities of TIL at 3–6 weeks of culture were 31.6 ± 15.8% (range 1.4–57.4%, n = 9) and 16.6 ± 11.6% (range 3.8–35.6%, n = 6), respectively. Autologous and allogeneic RCC cytotoxicity of TIL at 3–4 weeks of culture were 17.9 ± 19.7% (range 0–47.6%, n = 4) and 18.9 ± 14.8% (range 0–47.3% n = 12) respectively. Since there was no statistical difference between them, autologous specific cytotoxicity was not demonstrated. From these result of the present study it is unlikely that most of effector cells of rIL-2-expanded TIL in autologous RCC lysis are major histocompatibility complex-restricted cytotoxic T cells. We concluded that it is doubtful whether TIL is significantly superior over LAK cells in immunotherapy of human RCC.

We describe a new plate replacement method using a resin frame to reposition the mandible in the position before reconstruction plate fracture.The patient was an 89-year-old male who underwent segmental mandibulectomy, neck dissection, pectoralis major flap reconstruction, and plate reconstruction for left mandibular gingival carcinoma. Two years and eight months after the surgery, the reconstruction plate fractured. A full-scale three-dimensional model (3D model) was created to make a resin frame based on computed tomography taken before the fracture. Wire-holding grooves and screw holes were added to the resin frame to reduce the mandible in the position before the reconstruction plate fracture. After the fractured plate was exposed, the resin frame and fractured plate were ligated with a wire using wire-holding grooves.Subsequently, the resin frame was secured to the mandible with screws, and the position of the mandible was secured.After removing the fractured plate, a pre-bent reconstruction plate was secured in its place. With conventional methods, it is difficult to achieve an accurate position for the mandible during surgery ; however, in the present case, the 3D model created based on previous CT data and the positional relationship replicated by the resin frame allowed favorable reproduction of the original mandibular position. The present method is useful for cases such as the present one, where the number of remaining teeth is limited and maxillomandibular fixation is not indicated.