Dobrzanski Mark J, Reome Joyce B, Hylind James C, Rewers-Felkins Kathleen A, Abdulsamad Khaliquzzaman, Adams Shawna L
Department of Internal Medicine, Texas Tech University School of Medicine, Amarillo, Texas 79106, USA.
Immunol Invest. 2008;37(4):315-38. doi: 10.1080/08820130802083762.
The chemotherapeutic agent methotrexate is widely used in the treatment of breast cancer. Although its mechanism-of-action has been defined, less is known about its interaction with Ag-specific T cell-mediated antitumor responses. Type 1 CD8 T cell-mediated immune responses (Tc1) are cytolytic, produce IFN-gamma and are associated with effective antitumor responses. Using a murine transgenic TCR tumor model, we show that single-dose-treatment with methotrexate enhanced CD8-mediated type 1 antitumor responses when administered three days prior to Tc1 effector cell transfer. Co-treatment with methotrexate not only enhanced donor Tc1 cell accumulation and persistence at sites of primary tumor growth, but also promoted elevated levels of activated CD25(+) expressing donor TIL cells. This correlated with a marked decrease in the appearance of endogenous differentiated (CD44(High)) CD3/CD8/CD49b and CD3/CD4/CD49b tumor-infiltrating effector T cells at both early (Days 1-8) and late (Days 12-20) stages following treatment when compared to that of corresponding groups receiving either MTX or Tc1 cell transfer alone. Moreover, such cellular response kinetics appeared to further correlate with the down-regulation of endogenous CD4/CD44(High)/CD49b effector T cells producing IL-10 and delays in tumor growth in vivo. This suggested that Ag-specific Tc1 cell transfer, in combination with chemotherapy, can enhance antitumor responses by modulating select CD49b-expressing T effector/memory cell subpopulations involved in homeostasis and immune tolerance within the tumor environment. These studies offer insight into mechanisms that enhance T cell-based immunotherapy in cancer. Supplementary materials are available for this article. Go to the publisher's online edition of Immunological Investigations for the following free supplemental resource(s): Addendum 1.
化疗药物甲氨蝶呤被广泛用于治疗乳腺癌。尽管其作用机制已明确，但关于它与抗原特异性T细胞介导的抗肿瘤反应之间的相互作用却知之甚少。1型CD8 T细胞介导的免疫反应（Tc1）具有细胞溶解作用，可产生γ干扰素，并与有效的抗肿瘤反应相关。利用小鼠转基因TCR肿瘤模型，我们发现，在Tc1效应细胞转移前三天给予单剂量甲氨蝶呤治疗，可增强CD8介导的1型抗肿瘤反应。甲氨蝶呤联合治疗不仅增强了供体Tc1细胞在原发性肿瘤生长部位的积累和持久性，还促进了表达活化CD25(+)的供体肿瘤浸润淋巴细胞水平的升高。这与治疗后早期（第1 - 8天）和晚期（第12 - 20天）内源性分化的（CD44(High)）CD3/CD8/CD49b和CD3/CD4/CD49b肿瘤浸润效应T细胞的出现显著减少相关，与单独接受甲氨蝶呤或Tc1细胞转移的相应组相比。此外，这种细胞反应动力学似乎进一步与产生白细胞介素-10的内源性CD4/CD44(High)/CD49b效应T细胞的下调以及体内肿瘤生长的延迟相关。这表明，抗原特异性Tc1细胞转移与化疗联合使用，可通过调节肿瘤环境中参与稳态和免疫耐受的特定表达CD49b的T效应/记忆细胞亚群来增强抗肿瘤反应。这些研究为增强癌症中基于T细胞的免疫治疗的机制提供了见解。本文提供补充材料。请访问出版商的《免疫调查》在线版获取以下免费补充资源：附录1。
