Many tumors are potentially immunogenic, as corroborated by the presence of tumor-specific immune responses in vivo. Nonetheless, spontaneous clearance of established tumors by endogenous immune mechanisms is rare. Thus, the focus of most cancer immunotherapy is to supplement essential immunogenic elements to boost tumor specific immunity. Why, then, has tumor immunotherapy resulted in a generally poor clinical efficiency? The reason may lie in the increasingly documented fact that tumors develop diverse strategies that escape tumor specific immunity. In this talk I will discuss Treg and Th17 cells, their regulation in the tumor microenvironment and their therapeutic relevance.

Treg cells: Tumors express a range of antigens including self-antigens. Regulatory T cells (Tregs) are critical for maintaining T cell tolerance to self-antigens. Tregs are thought to dampen tumor associated antigen (TAA)-specific T cell immunity and to be the main obstacle tempering successful immunotherapy and active vaccination. Tregs accumulate within the tumor environment, and inhibit TAA-specific cytotoxicity and contribute to tumor growth in vivo, and predict a striking reduction of cancer patient survival. There are four potential sources for CD4+ Tregs in the tumor environment. (i). Trafficking. CD4+ Tregs from the thymus, lymph nodes, bone marrow and peripheral blood traffic into the tumor. CD4+ Tregs express CCR4, and abundant expression of CCL22 in the ovarian tumor environment stimulates Treg tumor infiltration. (ii). Differentiation. The tumor environment contains molecules capable of suppressing APC differentiation and function. These induce dysfunctional APCs, which in turn stimulate Treg differentiation. (iii). Expansion. Antigen presenting cells (APCs) including dendritic cells (DCs) and myeloid cells can stimulate Treg expansion and it is predicted that APCs in the tumor environment and draining lymph nodes may also induce Treg expansion. (iv). Conversion. Conventional T cells can be converted into Tregs by TGF-β, and high levels of TGF-β are often found in the tumor environment.

B7-H4 and Tregs: Tregs apply multiple modes of suppressive mechanisms in variable pathologic situations. Tregs can mediate immunosuppression at the level of APCs. For example, high numbers of B7-H4+ macrophages are found in ovarian tumor environments. Tumor B7-H4+ macrophages induced T cell cycle arrest and inhibited TAA-specific T cell responses through B7-H4. Interestingly, CD4+ Tregs triggered APC IL-10 production, induced B7-H4 expression on APCs through IL-10, and rendered APCs immunosuppressive through B7-H4. CD4+ Tregs may convey suppressive activity to APCs by stimulating B7-H4 expression. This suppressive mechanism may occur in the tumor environment including human ovarian cancer.

Th17 cells: Although an understanding of the role during cancer development and progression has been elusive, the frequent presence of inflammatory immune cells and molecular mediators in tumors has been recognized for over a century. Tumor has therefore been considered as a chronic inflammatory disease. IL-17 is a master proinflammatory cytokine. An effector CD4+ T cell lineage, IL-17 producing subpopulation, called Th17 has recently been described. Th17 cells play an active role in inflammation and autoimmune diseases. However, the nature, regulation and role of Th17 in the context of tumor immunity remain unknown. In this talk, I will discuss the kinetic distribution and phenotype of Th17 cells in multiple tumor microenvironments in mice and humans. We will compare the distribution and regulation of Tregs and Th17 cells in the tumor environments, and provide evidence supporting the concept that Treg and Th17 cells may be largely controlled by local environmental cytokines.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA