Title:
Effective cancer immunotherapy by targeting regulatory T cells

Hiroyoshi NISHIKAWA, MD, PhD.
Associate Professor,
Experimental Immunology, Immunology Frontier Research Center ,
Osaka University

※時間と会場にご注意ください　16:00～17:00　医学教育図書棟３階　第２講義室

Abstract:
Regulatory T cells (Tregs) play a critical role for suppressing self-reactive T cells present in the normal immune system. A large number of human tumor-associated antigens identified to date are antigenically normal self-constituents, and tumor immunity is in part a form of autoimmunity. Therefore, m echanisms for maintaining immunological self-tolerance such as Tregs could hinder effective anti-cancer immunity. Indeed, the numbers of FOXP3⁺ CD25⁺ CD4⁺ Tregs present in tumors and, in particular, decreased ratios of CD8⁺ T cells to FOXP3⁺ CD25⁺ CD4⁺ Tregs in tumors, correlate with poor prognosis in various types of human cancer. In addition, while NY-ESO-1 (a cancer/testis antigen)-specific CD4⁺ T cells are present even in healthy individuals, the priming of NY-ESO-1-specific CD4⁺ T cells is rigorously suppressed by CD25⁺ CD4⁺ Tregs.
FOXP3 expression is induced in naive CD4⁺ T cells by T-cell receptor stimulation in humans and the presence of this non-regulatory FOXP3-expressing CD4⁺ T cell population in the periphery 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 molecules for Treg manipulation. We have shown that human Foxp3⁺ CD4⁺ T cells are composed of three subsets; CD45RA⁺ Foxp3 lo naive Tregs (Fr. I), CD45RA – Foxp3 hi effector Tregs (Fr. II), and CD45RA – Foxp3 lo non-Tregs (Fr. III). 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. These tumor infiltrating effector Tregs dominantly expressed CCR4, proposing CCR4 as a possible target for Treg control.
Here, I would like to discuss how Tregs accumulate in tumors and gain effector phenotypes and how to control these Tregs.

References:
1. Nishikawa H et al; C ancer/testis antigens are novel targets of immunotherapy for adult T-cell leukemia/lymphoma. Blood. 119:3097-3104 2012

2. Nishikawa H and Sakaguchi S.; Regulatory T cells in Tumor Immunity. Int J Cancer. 127:759-767 2010 .

3. Nishikawa H et al; CD4⁺ CD25⁺ regulatory T cells control the induction of antigen-specific CD4⁺helper T cell responses in cancer patients. Blood. 106: 1008-1011 2005 .

4. Nishikawa Het al; Definition of target antigens for naturally occurring CD4⁺ CD25⁺ regulatory T cells. J Exp Med. 201: 681-686, 2005.