Immune recognition of tumors in an antigen-specific manner was first illustrated by experiments involving transplantation of chemically induced tumors into laboratory mice [1, 2]. Specifically, the growth of a transplanted tumor could be prevented by prior exposure to the same tumor, but not a different tumor. Many investigators have since observed naturally developing tumor-specific T cell responses (reviewed in ) which, in patients treated with standard therapies, correlate with improved prognosis [4-10]. Despite this positive correlation, the tumor infiltrating lymphocytes (TIL) do not always control tumor growth. Tumor-specific T cells are ineffective in part due to active regulation and suppression by tumors. For example, tumors produce the tryptophan degrading enzyme indoleamine 2,3-dioxygenase that inhibits T cell proliferation . In addition, tumors produce immune suppressive cytokines such as TGFβ [12, 13] and IL-10 . The mechanism of immune suppression by these cytokines includes the inhibition of proliferation and inflammatory cytokine production by immune cells. For detailed reviews of tumor-induced immune suppression see the other reviews in this issue and .
In this review, we focus on another mechanism responsible for the poor reactivity of the tumor-specific T cell repertoire, the low functional avidity of the responding T cells. Functional avidity, or the sensitivity of T cell to antigen, is an important factor influencing the efficacy of a T cell response. Virus-specific cytotoxic T lymphocytes (CTL) with high functional avidity clear viral infections better than T cells with low functional avidity because these CTL are more sensitive to small viral loads [16, 17]. Analysis of the functional avidity of tumor-specific T cells has provided insight into why tumors develop despite the presence of TIL and how these T cells may be harnessed for cancer therapies. In this review we will discuss the factors influencing the functional avidity of CTL and how this affects the T cell response to tumors. Furthermore, we will discuss different approaches aimed at improving the functional avidity of the tumor-specific T cells with the goal of augmenting conventional treatments and T cell therapies against cancer.