Control of Tumor-Associated Regulatory T Cells for Effective Cancer Immunotherapy
Hiroyoshi Nishikawa 1Division of Cancer Immunology, Research Institute/EPOC, National Cancer Center, Tokyo/Chiba, Japan; 2Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
There are two types of tumor antigens: tumor-specific antigens (TSAs), which are either oncogenic viral proteins or abnormal proteins stemming from somatic mutations (neoantigens), and tumor-associated antigens (TAAs), which are highly or aberrantly expressed normal proteins. It is not yet determined how CD8+ T cells specific for each type of antigen contribute to clinical tumor regression and whether activation of these self vs non-self antigen specific CD8+ T cells are controlled differently. FoxP3+CD4+ regulatory T cells (Tregs) inhibit anti-tumor immune responses. To address the differences of regulatory T-cell (Treg) suppression to these antigens, Melan-A (a representative TAA)- and CMV (a surrogate TSA)-specific CD8+ T cells were stimulated in the presence of Tregs. Tregs rendered Melan-A-specific T cells anergic. In contrast, while CMV-specific CD8+ T cells proliferated in the presence of Tregs, they highly expressed co-inhibitory molecules such as PD-1, suggesting the importance of anti-PD-1 mAb for unleashing anti-tumor activity by neoantigen-specific CD8+ T cells. Thus, developing novel strategies to control Tregs, particularly in cancers that do not contain large numbers of TSAs (neoantigens) could be important for effective cancer immunotherapies. In humans, FoxP3expression is induced in naive CD4+ T cells upon T-cell receptor stimulation, and the presence of this non-regulatory FoxP3-expressing CD4+ T cells in the periphery has compromised the identification of Tregs. Hence, establishing strategies to identify bona fide Tregs which suppress effective anti-tumor immune responses is important, particularly for exploring specific strategies for Treg manipulation. FoxP3+CD4+ T cells can be dissected into three subpopulations by the expression levels of FoxP3 and CD45RA: FoxP3loCD45RA+ cells (naïve Tregs), FoxP3hiCD45RA- cells (effector Tregs), and FoxP3loCD45RA- non-Tregs. Tumor-infiltrating T cells contained a higher frequency of effector Tregs (Fr. II) compared with peripheral blood. Correspondingly, Tregs with a naive phenotype (Fr. I) were barely detected in tumors while peripheral blood contained both naive and effector Tregs. Effector Tregs harbored certain phenotypes compared with naive Tregs, such as higher expression of CCR4. Selective depletion of eTregs by targeting the phenotypes with antibodies or signal inhibitors (such as TKIs) and subsequent in vitro antigen stimulation, effectively activated tumor (self)-antigen-specific T cells. Therefore, selective depletion methods of effector Tregs, rather than whole Tregs, are promising novel strategies for cancer immunotherapy.
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