Cancer-Induced Signaling Defects in Antitumor T Cells

Immune responses to tumor antigens are seen in almost all cancers but, since growth is usually progressive, are clearly ineffective in elimination of the tumor (Parmiani et al., 2003). Understanding the biochemical basis for escape from anti-tumor immunity guides multiple avenues of research endeavor. Failure to eliminate tumors can be potentially explained by a variety of reasons, any or all of which may permit escape from immune-mediated eradication (Rabinovich et al., 2007). The possibilities can be broadly grouped into two categories: inhibition of the antitumor priming phase or inhibition of the effector phase. Antitumor Ig and T cells are found in patients and in animal models proving that some measurable priming occurs during tumor growth (Frey and Monu, 2006; Radoja et al., 2000). That the magnitude of a given antitumor response is clearly less robust in comparison to that detected after microbial infection (where, for example, up to 10 % of circulating T cells can be reactive with Epstein–Barr virus proteins) has been interpreted to mean that tumors grow faster than the immune response can contend with. This notion is overly simplistic since human tumors grow quite slowly and there is clearly inhibition of both expansion in number and function of anti-tumor T cells (see below). The notion that priming of antitumor T cells is defi-cient during tumor growth is supported by findings that the frequency of tumor-specific T cells can be considerably increased in patients receiving experimental immunotherapy. Unfortunately, in spite of greater numbers of antitumor effector T cells in the blood of vaccinated patients (that secrete IFN-γ in response to recognition of cognate antigen in vitro), tumors are often not eliminated (Rosenberg et al., 2004). This observation suggests that experimental vaccination in human cancer is imperfect/inadequate, a reasonable interpretation considering the advanced state of disease which patients must demonstrate in order to qualify for experimental therapy and which motivates the pursuit of better candidate vaccines. Alternatively there may be immunesuppression and/or immune tolerance in the tumor microenviron-ment, the draining LN or systemically which impedes the function of the antitumor T cells induced by vaccination, also a reasonable interpretation (Frey and Monu, 2006). Antigen-specific tolerance to tumor antigens can be induced by tumor growth (Cuenca et al., 2003; Lee et al., 1999; Overwijk et al., 2003; Willimsky and Blankenstein, 2005) and, since many tumor antigens have been shown to be self-derived differentiation antigens, has focused much attention on attempts to overcome anergy (Pardoll, 2003). The anergic phenotype of antitumor T cells is complex: adoptive transfer of naive T cells reactive to a model xenogenic tumor antigen could expand in tumor-bearing mice implying priming in vivo (Staveley-O’Carroll et al., 1998). However, the T cells did not respond to subsequent in vivo vaccination, a finding that was interpreted to mean that initial encounter with antigen induces anergy. Induced anergy is not a function of T-cell differentiation status since similar results using memory or effector T cells in adoptive transfer protocols have been reported (Horna et al., 2006). A prominent role for CD4+CD25+ TReg in anergy induction following vaccination has been shown (Gattinoni et al., 2006) and abundant TReg are found in some tumors (Curiel et al., 2004), inspiring efforts that attempt to either eliminate or block TReg activity concurrent with vaccination (Zou, 2005). Although prominent, the role of TReg in causing antitumor T-cell dysfunction in vivo is possibly not exclusive since considerable antigen-specific cells are found not activated in situ (Zhou et al., 2006). This observation supports the notion that dendritic cell function (antigen processing and/or cell activation) is likely to be deficient, a topic both recently reviewed (Bronte et al., 2006; Gabrilovich, 2004) and vigorously pursued. Another observation suggestive that priming is defective in tumor-bearing hosts is that several HLA Class I-restricted tumor antigens have been identified (using antitumor TIL as the basis of tumor cDNA expression systems) that are products of tumor-specific mishandling of genetic information—faulty mRNA transcription, splicing or translation (Coulie et al., 1995; Dolcetti et al., 1999; Guilloux et al., 1996; Ishikawa et al., 2003; Lupetti et al., 1998). Originally proposed by T. Boon in 1989 (Boon and Van Pel, 1989), to considerable skepticism (Lindahl, 1991), these antigens are expressed from alternative reading frames or intronic sequences. Clearly these antigens are not “self” and their cognate TCR are therefore likely to be of relatively high affinity. Thus, those T cells probably are not subject to the regulatory constraints imposed by the clonal selection theory on self-reactive T cells in the periphery whose TCR affinity for cognate antigen is modest. Although not directly assessed, the abundance of this class of antitumor T cell is probably low in situ which implies either that the precursor frequency is low or priming of the cognate T cells is deficient. (Their effector-phase functions are also clearly suppressed since tumors grow, implying a second level of defect, discussed in detail below. However, two reports showed enhanced death of cancer cells proximal to CD8+ T cells in tumors having increased microsatellite instability encouraging the notion that antitumor TIL in situ can in some cases express lytic function (Dolcetti et al., 1999; Ishikawa et al., 2003).) Evidence for defective T-cell priming in tumor-bearing hosts is abundant and it undoubtedly contributes to modest (or failed) antitumor T-cell immune response (discussed in other chapters); nevertheless, since there is demonstrable antitumor immune responses some priming must occur. Antitumor T cells are found in patient blood, LN and tumor tissue but are defective in response to stimulation through the TCR: cytokine release, lytic function and proliferation are often deficient (Whiteside and Parmiani, 1994); the extent of deficiency is dependent upon tumor type and stage, and the type of assay employed. These defects may be explained by several potential mechanisms that can be generalized as (1) the absence of a positive activation signal, i.e., antigen (or costimulation) or (2) the presence of a negative signal, i.e., enhanced (and dominant) activity of an inhibitory signaling receptor or soluble mediator (e.g., PD-1 or TGFβ-1). This latter notion is reminiscent of the phenotype of T cells in response to agonist plus antagonist peptides, or perhaps only partial agonist peptide (Sloan-Lancaster et al., 1996; Sloan-Lancaster et al., 1996). There is clearly tumor antigen present in the body, since tumors are usually clinically discernible, thus the absence of antigen is not the basis for the non-activated state of antitumor T cells (although processing and presentation by dendritic cells may be impaired). Also, deficient costimulation (by APC) possibly contributes to the limited magnitude of priming. Therefore, albeit not maximally expanded in number, antitumor T cells in the circulation and tumor tissue have suppressed immune responses likely due to some form of inhibition. This review analyzes the data concerning tumor-induced inhibition of antitumor T-cell function.