Department of Oral and Maxillofacial Surgery, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.
Department of Tumor Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
Int J Oncol. 2017 Nov;51(5):1471-1481. doi: 10.3892/ijo.2017.4142. Epub 2017 Oct 2.
FP treatment, which combines 5-fluorouracil (5-FU) and cisplatin (CDDP) chemotherapy, is widely used for treatment of advanced head and neck cancer (HNC). It has been suggested that these drugs cause immunomodulation in the cancer microenvironment, for example, downregulation of immunosuppressive cells such as regulatory T-cells (Tregs) and myeloid-derived suppressive cells (MDSCs), activating dendritic cells (DCs), and upregulation of tumor antigens and major histocompatibility complex (MHC) molecules in cancer cells leads to enhancement of cancer immunity, which is important in cancer treatment, as well as providing a direct killing effect. Therefore, development of chemoimmunotherapy by combining FP treatment with immunotherapy for HNC has become a recent challenging issue. However, the direct effects of these drugs on immune effector cells, especially cytotoxic T-lymphocytes (CTLs), are not well known. We have investigated the direct actions of these drugs on CTL functions in in vitro experiments using cytomegalovirus (CMV) pp65 antigen-specific CTLs (CMVpp65-CTLs) and oral squamous cell cancer (OSCC) cell lines overexpressing CMVpp65 antigen as target cells. Although CDDP partially inhibited proliferation of memory CMVpp65-CTL in peripheral blood, the proliferation was not inhibited by 5-FU. Cytotoxicity and the IFN-γ release response of the CMVpp65-CTLs were not inhibited by these drugs, and it is important to note that these drugs, especially 5-FU, sensitized OSCC cell lines to CMVpp65-CTL. Furthermore, CMVpp65-CTL cytotoxicity to CDDP-resistant OSCC cells, HSC-3/CDDP-R1, was the same as the cytotoxicity to the parental cells. Thus, we suggest that combined immunotherapy with FP treatment is an effective novel HNC treatment.
FP 治疗方案结合了氟尿嘧啶（5-FU）和顺铂（CDDP）化疗，广泛用于治疗晚期头颈部癌症（HNC）。有人提出，这些药物会在癌症微环境中引起免疫调节，例如下调调节性 T 细胞（Tregs）和髓系来源的抑制性细胞（MDSCs）等免疫抑制细胞，激活树突状细胞（DC），上调癌细胞中的肿瘤抗原和主要组织相容性复合体（MHC）分子，从而增强癌症免疫，这对头颈部癌症的治疗很重要，同时也提供了直接的杀伤作用。因此，通过将 FP 治疗与头颈部癌症的免疫治疗相结合来开发化疗免疫治疗已成为当前的一个挑战。然而，这些药物对免疫效应细胞，特别是细胞毒性 T 淋巴细胞（CTL）的直接作用尚不清楚。我们在体外实验中使用巨细胞病毒（CMV）pp65 抗原特异性 CTL（CMVpp65-CTL）和过表达 CMVpp65 抗原的口腔鳞状细胞癌细胞系（OSCC）作为靶细胞，研究了这些药物对 CTL 功能的直接作用。虽然 CDDP 部分抑制了外周血中记忆性 CMVpp65-CTL 的增殖，但 5-FU 并未抑制其增殖。这些药物并未抑制 CMVpp65-CTL 的细胞毒性和 IFN-γ 释放反应，值得注意的是，这些药物特别是 5-FU，使 OSCC 细胞系对 CMVpp65-CTL 敏感。此外，CMVpp65-CTL 对 CDDP 耐药的 OSCC 细胞，HSC-3/CDDP-R1 的细胞毒性与对亲本细胞的细胞毒性相同。因此，我们认为，与 FP 治疗相结合的免疫联合治疗是一种有效的新型头颈部癌症治疗方法。
