Target Density, Not Affinity or Avidity of Antigen Recognition, Determines Adoptive T Cell Therapy Outcomes in a Mouse Lymphoma Model

CTL公司* 贪婪 淋巴瘤 癌症研究 免疫学 过继性细胞移植 T细胞受体 细胞毒性T细胞 抗原 T细胞 生物 医学 免疫系统 CD8型 体外 生物化学
作者
Gabriela Segal,Sandro Prato,Dietmar Zehn,Justine D. Mintern,José A. Villadangos
出处
期刊:Journal of Immunology [American Association of Immunologists]
卷期号:196 (9): 3935-3942 被引量:13
标识
DOI:10.4049/jimmunol.1502187
摘要

Abstract Adoptive T cell therapy (ACT) with antitumor CTL is a promising and tailored treatment against cancer. We investigated the role played by the affinity and avidity of the interaction between the tumor and the CTL on the outcome of ACT against a mouse non-Hodgkin B cell lymphoma that expresses OVA as a model neoantigen. ACT was assessed under conditions where antitumor CTL expressed TCR of varying affinity for OVA. We also assessed conditions where the avidity of Ag recognition varied because the lymphoma cells expressed high or low levels of OVA. Efficient eradication of small tumor burdens was achieved by high- or low-affinity CTL. Tumors expressing low levels of OVA could also be eliminated. However, ACT against large tumor burdens was unsuccessful, accompanied by CTL deletion and functional impairment. This negative outcome was not prevented by lowering the affinity of the CTL or the expression of OVA in the lymphoma. Thus, tumor burden, rather than CTL affinity or avidity, appears to be the main determinant of ACT outcomes in our lymphoma model. Insofar as our results can be extrapolated to the clinical setting, they imply that the range of CTL and tumor-associated Ag combinations that may be effectively harnessed in ACT against lymphoma may be wider than generally assumed. CTL expressing low-affinity TCR may be effective against lymphoma, and lowly expressed tumor-associated Ag should be considered as potential targets, but tumor reduction should always be implemented before infusion of the CTL.
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