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Perspectives of T Cells in Tumor Immunology

¹ Institute of Immunology, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany and ² Department of Immunology, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, P.R. China

Requests for reprints: Dieter Kabelitz, Institute of Immunology, University Hospital Schleswig-Holstein Campus Kiel, Michaelisstr. 5, D-24105 Kiel, Germany. Phone: 49-431-5973340; Fax: 49-431-5973335; E-mail: kabelitz{at}immunologie.uni-kiel.de.

	Abstract

Top Abstract Introduction Tumor-Expressed Antigens... Modulation of {gamma}{delta} T... Perspectives of {gamma}{delta} T... Potential Obstacles of... Conclusion and Future Directions References

 
Subsets of human T cells recognize tumor cell–expressed ligands that are not seen by the T-cell receptor of conventional ß T cells. V1 T cells recognize MHC class I chain–related molecules A and B and UL-16–binding proteins expressed at variable levels on epithelial tumor cells and some leukemias and lymphomas. In addition, therapeutically used aminobisphosphonates and synthetic phosphoantigens activate V2 T cells, the dominant subset of T cells in human peripheral blood that display strong cytotoxicity towards various epithelial tumors. Intentional activation of T cells in vivo and/or adoptive cell therapy with in vitro expanded T cells holds considerable promise as a novel immunotherapy in certain types of cancer. [Cancer Res 2007;67(1):5–8]

	Introduction

Top Abstract Introduction Tumor-Expressed Antigens... Modulation of {gamma}{delta} T... Perspectives of {gamma}{delta} T... Potential Obstacles of... Conclusion and Future Directions References

 
T cells carrying the T-cell receptor (TCR) account for 2% to 5% of CD3⁺ T cells in the peripheral blood but constitute a major T-cell subset in other anatomic localizations, such as the intestine or the skin (here, however, only in the murine but not in human skin; ref. 1). In the blood of most healthy individuals, T cells expressing the V2 gene paired with one particular V chain (V9) account for 50% to >90% of the T-cell population. In contrast, intestinal intraepithelial T cells frequently express the V1 gene, which can associate with different V elements (1).

An obvious question is why the immune system has afforded to maintain two different types of TCR throughout evolution. There are no major differences between ß and T cells with regard to effector functions. Thus, activated T cells have strong cytotoxic effector activity (using both death receptor/death ligand and cytolytic granule pathways) and produce various cytokines (frequently including tumor necrosis factor- and IFN-; ref. 1). It seems, however, that the TCR recognizes novel ligands that are not seen by ß T cells, thereby providing an essential additional pathway of local immunosurveillance with immediate relevance for tumor defense (1, 2). In addition, increasing evidence indicates that T cells also play a nonredundant role in the antimicrobial immune defense through the selective recognition of bacterial metabolites and some viral antigens (1, 3). Most T cells lack cell surface expression of CD4 or CD8, in agreement with their MHC-nonrestricted recognition of such unconventional antigens.

	Tumor-Expressed Antigens Recognized by the TCR of Human T Cells

Top Abstract Introduction Tumor-Expressed Antigens... Modulation of {gamma}{delta} T... Perspectives of {gamma}{delta} T... Potential Obstacles of... Conclusion and Future Directions References

 
V1 T cells recognize MHC class I chain–related molecules A and B and UL-16–binding proteins. V1 T cells isolated from tumor-infiltrating lymphocytes (TIL) of patients with colorectal cancer have been shown to lyse not only autologous but also various allogeneic epithelial tumor cells (4). The MHC class I chain–related molecules A and B (MICA and MICB) and the UL-16 binding proteins 1 to 3 (ULBP1–3) can be induced on epithelial cells by heat shock or oxidative stress and are constitutively expressed to variable levels on many epithelial tumor cells and also on some leukemias and lymphomas. Such MICA/MICB or ULBP-expressing tumor and lymphoma cells are recognized and killed by V1 T cells (5, 6). It has been debated whether MICA/MICB and ULBPs are directly recognized by the V1 TCR or, alternatively, activate V1 T cells through alternative receptors, such as stimulatory natural killer (NK) receptors (see below). Although this issue is unresolved for the ULBPs, two lines of evidence suggest direct recognition of MICA by the V1 TCR (Fig. 1A ). First, MICA tetramers bind to TCR transfectants expressing the relevant V1 TCR but lacking NKGD2, the activating NK receptor for MICA (7). Second, we have recently generated soluble recombinant V1 TCR protein from MICA-reactive V1 T cells. The soluble V1 TCR, but not similarly constructed control V2 or V3 TCR proteins, specifically bound to immobilized recombinant MICA protein as shown by surface plasmon resonance (8). Hence, it seems that tumor-expressed MICA/MICB antigens can be specifically recognized by the TCR of human V1 T cells. It is quite likely, however, that the V1 TCR recognizes additional as yet undefined tumor cell ligands (Fig. 1A).

View larger version (58K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Tumor cell ligands recognized by human T cells and strategies for T cell–based immunotherapy. Left panel, the dominant population of V2V9 T cells recognizes via its TCR nonpeptidic phosphoantigens, such as the naturally occurring isoprenoid metabolite IPP, the synthetic bromohydrin pyrophosphate (BrHPP; Phosphostim), aminobisphosphonates (N-BP), the ectopically expressed F1-ATPase, and apolipoprotein A-I. Ligands recognized by the V1 TCR have been less well defined but include MICA. In addition, MICA/MICB and ULBPs frequently expressed on tumor cells are ligands for the activating NK receptor NKG2D, which is present on V1 and V2 T cells. Right panel, strategies for T cell–based immunotherapy include (i) the adoptive cell transfer of in vitro expanded T cells and (ii) the in vivo activation of V2V9 T cells by phosphoantigens (e.g., bromohydrin pyrophosphate/Phosphostim) or aminobisphosphonates and low-dose IL-2. V2V9 T cells can be readily activated and expanded in vitro by phosphoantigens (bromohydrin pyrophosphate) or aminobisphosphonates in the presence of IL-2. Possible beneficial effects of additional NKG2D stimulation by activating antibodies or naturally occurring NKG2D ligands require further investigation. In the absence of defined ligands (except for MICA) that are recognized by the V1 TCR, tumor-reactive V1 T cells can be activated and expanded in vitro by stimulation with mitogenic anti-TCR antibodies and IL-2 in the absence or presence of additional NKG2D ligation.

V2 T cells recognize phosphoantigens and ectopically expressed mitochondrial ATPase.

In addition to the phosphoantigens, the very same V2V9 TCR also recognizes a mitochondrial F1-ATPase–related structure and delipidated apolipoprotein A-I, which are expressed on the surface of tumor cells (13). Thus, it is striking to note that one single molecularly defined TCR (i.e., V2V9) recognizes structurally completely unrelated moieties, such as isoprenoid metabolites, F1-ATPase, and apolipoprotein A-I, all of which play a role as tumor antigens and contribute to the antitumor reactivity of human T cells (see Fig. 1A). To identify possible additional tumor cell ligands for V2 T cells, we have synthesized peptides corresponding to the V2 CDR3 region of ovarian epithelial carcinoma–infiltrating T cells. Such V2 CDR3 peptides and recombinant V2 CDR3-grafted antibodies bind to certain epithelial tumor cells and tumor cell lysates, indicating the direct involvement of the TCR V2 region in tumor cell recognition (14). In ongoing investigations, we use the CDR3 peptides and the CDR3-grafted recombinant antibodies in an attempt to identify the bound tumor cell ligands.

	Modulation of T-Cell Activation by NK Receptors

Top Abstract Introduction Tumor-Expressed Antigens... Modulation of {gamma}{delta} T... Perspectives of {gamma}{delta} T... Potential Obstacles of... Conclusion and Future Directions References

 
T-cell responses are modulated by activating and inhibitory NK receptors, which have been first identified on NK cells but are also present on T-cell subsets, notably CD8⁺ ß T cells and T cells. Many NK receptors recognize MHC class I molecules as ligands and signal through their immunoreceptor tyrosine–based activation motifs (activating receptors) or immunoreceptor tyrosine–based inhibitory motifs (inhibitory receptors). Of special relevance for T cells is the activating NKG2D receptor as it is expressed on many T cells. NKG2D interacts with MICA/MICB and ULBPs frequently expressed on tumor cells and thus can interfere with TCR-dependent signaling events in tumor-reactive T cells. As discussed above, there is good evidence that the V1 subset recognizes MICA/MICB (but not ULBPs) directly via the TCR. Therefore, NKG2D-positive V1 T cells might recognize MICA/MICB–expressing tumor cells simultaneously through the TCR and NKG2D, and both pathways likely contribute to cellular activation and tumor cell lysis (Fig. 1A). NKG2D, however, is also expressed on V2 T cells. In these instances, the TCR-dependent recognition of unusual ligands described above and the subsequent activation of V2 T cells can be enhanced by MICA engagement of NKG2D (15). Importantly, however, NKG2D-positive V2 T cells can also be directly activated by MICA in the absence of TCR-dependent ligand recognition (16). Irrespective of the additional complexity due to the effect of MHC class I–specific inhibitory NK receptors, these results point to possible strategies of exploiting the NKG2D receptor as a target for activation and expansion of tumor-reactive V2 T cells.

	Perspectives of T Cells for Immunotherapy of Cancer

Top Abstract Introduction Tumor-Expressed Antigens... Modulation of {gamma}{delta} T... Perspectives of {gamma}{delta} T... Potential Obstacles of... Conclusion and Future Directions References

 
Tumor-infiltrating T cells are tumor reactive. T cells have been consistently identified and isolated from TIL in various types of cancer, including colorectal, breast, prostate, ovarian, and renal cell carcinoma (4, 5, 9, 12, 14). T cell lines and clones established from TIL recognize and kill not only the autologous tumor but generally also a broad range of related tumors, presumably due to the recognition of shared ligands as described above. Importantly, the T cells preferentially kill tumor cells and show low (if any) reactivity towards nontransformed cells, a feature that has raised great interest to explore their therapeutic potential (9, 12).

Tumor-reactive T cells are stimulated by phosphoantigens and aminobisphosphonates. Synthetic phosphoantigens, such as bromohydrin pyrophosphate (Phosphostim) and aminobisphosphonates, are potent activators of V2V9 T cells. In the presence of interleukin-2 (IL-2), these ligands induce a rapid and exponential expansion of T cells to large cell numbers for potential application in adoptive cell transfer (9). In vitro expanded V2V9 T cells maintain their antitumor activity in vivo upon adoptive transfer into immunodeficient mice transplanted with human tumor cells, indicating the feasibility of this approach in a preclinical model (17). Therefore, two strategies for the potential usage of T cells in tumor immunotherapy are presently being envisaged i.e., the adoptive cell transfer of in vitro expanded T cells and the in vivo therapeutic application of -stimulating phosphoantigens or aminobisphosphonates together with low-dose IL-2 (Fig. 1B). Ongoing clinical phase I trials evaluate Phosphostim together with low-dose IL-2 in patients with renal cell carcinoma (18), and other types or cancer, including pancreatic adenocarcinoma and colon carcinoma, are under consideration. Trials with aminobisphosphonates plus IL-2 are also done in multiple myeloma (11).

	Potential Obstacles of T Cell–Based Immunotherapy

Top Abstract Introduction Tumor-Expressed Antigens... Modulation of {gamma}{delta} T... Perspectives of {gamma}{delta} T... Potential Obstacles of... Conclusion and Future Directions References

 
As discussed above, tumor-expressed MICA/MICB and ULBPs trigger T-cell activation via the TCR and/or NKG2D. These NKG2D ligands can be proteolytically shed from the surface of tumor cells, and the soluble NKG2D ligands have been shown to inhibit NK cell and CD8 T-cell function through the down-modulation of NKG2D. Soluble MICA present in the serum of tumor patients has recently been found to down-regulate also the cytotoxic activity of T cells (19). Moreover, sustained activation of NKG2D by MICA is known to inhibit NKG2D-expressing cytotoxic cells. Therefore, therapeutic approaches have to consider that tumor-derived soluble NKG2D ligands might interfere with T-cell immunotherapy in tumor patients.

Moreover, it is obvious that T cells are part of the multicellular immune system that is tightly regulated by multiple pathways, including regulatory T cells (Treg). Therefore, T cell–based immunotherapies (like any other cellular therapy, including dendritic cell vaccination) should also consider the possible negative effect of Treg on the generation of effective antitumor responses (20). Presently, it is unknown to what extent the activation of T cells is controlled by naturally occurring Treg. Our own preliminary results suggest that the in vitro activation of human T cells in response to phosphoantigens is enhanced in the absence of CD4⁺CD25^high Treg, supporting the idea that dampening of Treg activity might be beneficial also in T cell–based immunotherapy of cancers (20).

	Conclusion and Future Directions

Top Abstract Introduction Tumor-Expressed Antigens... Modulation of {gamma}{delta} T... Perspectives of {gamma}{delta} T... Potential Obstacles of... Conclusion and Future Directions References

 
The identification of unusual tumor-expressed ligands that are recognized by but not by conventional ß T cells together with their potent cytotoxic antitumor effector activity have recently stimulated great interest in the development of T cell–based immunotherapies in certain types of cancer, such as renal cell carcinoma, colon carcinoma, pancreatic adenocarcinoma, multiple myeloma, and certain leukemias. In contrast to other potential effector cells, it is possible to envisage combined in vivo activation and adoptive cell therapy with ex vivo expanded T cells because aminobisphosphonates and IL-2 are licensed for clinical application (and Phosphostim is in clinical trials). Although T cells are thus an attractive target for cellular immunotherapy, protocols for their therapeutic use need to be optimized. In this regard, it could be explored whether activating anti-NKG2D antibodies might help to costimulate T-cell expansion in vitro to obtain the large cell numbers required for adoptive cell transfer (Fig. 1B). Future studies should also address the possible advantage of combining T cell–based immunotherapy with conventional chemotherapy or other therapeutic approaches, such as antiangiogenic drugs.

	Acknowledgments

 
Grant support: Deutsche Forschungsgemeinschaft grant Ka 502/8-3 (D. Kabelitz); National Program for Key Basic Research Projects, Ministry of Science and Technology of P.R. China grants 2001CB510009 and 2004CB518706; and National Natural Science Foundation of P.R. China grant 30490244 (W. He).

Received 8/18/06. Revised 10/ 6/06. Accepted 11/ 7/06.

	References

Top Abstract Introduction Tumor-Expressed Antigens... Modulation of {gamma}{delta} T... Perspectives of {gamma}{delta} T... Potential Obstacles of... Conclusion and Future Directions References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kabelitz, D. Articles by He, W. Search for Related Content PubMed PubMed Citation Articles by Kabelitz, D. Articles by He, W. Related Collections Cancer Immunology Cancer Immunology: Innate Immunity