Abstract IA12: Targeting regulatory T cells for cancer immunotherapy
Authors: Sakaguchi Shimon 
Published: November 2016

Abstract
Naturally occurring regulatory T (Treg) cells, which express the transcription factor Foxp3, are indispensable for immunological self-tolerance and immune homeostasis. They also hinder effective tumor immunity and can therefore be targeted to evoke anti-tumor immune responses by reducing them or attenuating their suppressive activity (1). Human Foxp3+ T cells are heterogenous in function and phenotype, including suppressive and non-suppressive populations (2, 3). Efforts to delineate these populations have shown that Foxp3+ cells in the peripheral blood can be separated into at least three functionally distinct subpopulations, including (i) highly proliferative and differentiated Foxp3-high population (designated effector Treg cells) with stable Treg-specific epigenome alterations, the majority of which will die by apoptosis after suppression, (ii) naïve Foxp3-low population (naïve Treg cells), which is in a resting state and upon TCR stimulation differentiates into effector Treg cells, and (iii) Foxp3-low non-suppressive population unstable in Treg-specific epigenome changes and capable of secreting pro-inflammatory cytokines. The three Foxp3+ T-cell subpopulations in the peripheral blood can be distinguished by a combination of expression levels of cell surface molecules such as CD45RA and CD15s (sialyl Lewis X); for example, effector Tregs are CD45RA−CD15s+; naïve Tregs CD45RA+CD15s−; non-Treg cells CD45RA−CD15s−. Each population exhibits distinct behavior in different disease states (2, 3).
There is accumulating evidence that abundant Treg cell infiltration into tumors is associated with poor clinical outcomes in various types of cancers. However, the role of Treg cells is controversial in colorectal cancers (CRCs), in which FOXP3+ T cell infiltration indicates better prognosis in some studies. We have recently shown that CRCs, which are commonly infiltrated by terminally differentiated and suppression-competent FOXP3hi Treg cells, can be classified into two types by the degree of additional infiltration of FOXP3lo nonsuppressive T cells capable of secreting inflammatory cytokines (4). Interestingly, CRCs with abundant infiltration of the latter show significantly better prognosis than those with predominant FOXP3hi Treg cell infiltration. Development of such inflammatory FOXP3lo non-Treg cells appears to depend on secretion of IL-12 and TGF-β by tumor tissues and to be correlated with tumor invasion by intestinal bacteria, especially Fusobacterium nucleatum. Thus, functionally distinct subpopulations of tumor-infiltrating FOXP3+ T cells contribute in opposing ways to determining CRC prognosis.
These results also indicate indicate that depletion of suppression-competent FOXP3hi effector Treg cells from tumor tissues is an effective treatment strategy for various cancers including CRC. Indeed, depletion of FOXP3hi effector Treg cells alone by administration of cell-depleting anti-CCR4 mAb is able to evoke effective tumor immunity without serious autoimmunity (5). Similarly, Imatinib, a tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, is able to evoke tumor immunity via specifically depleting effector Treg cells as an off target effect (unpublished). Taken together, Treg depletion by biologicals or small molecules, together with other treatments to activate effector T cells (e.g., tumor antigen vaccination or immune checkpoint blockade) can be an effective way of cancer immunotherapy.
References
1. Nishikawa H, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Curr Opin Immunol 2014;27:1-7.2. Miyara, M, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009;30:899-911. 3. Miyara M, et al. Sialyl Lewis x (CD15s) identifies highly differentiated and most suppressive FOXP3high regulatory T cells in humans. Proc Natl Acad Sci USA 2015;112:7225-7230. 4. Saito T, et al. Two FOXP3+CD4+ T-cell subpopulations distinctly control the prognosis of colorectal cancers. Nature Med 2016;22:679-684. 5. Sugiyama D, et al. Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc Natl Acad Sci USA 2013;110:17945-17950.
Citation Format: Shimon Sakaguchi. Targeting regulatory T cells for cancer immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA12.