SUMMARY CD8+ T cells recognizing tumor-specific antigens are detected in cancer patients but are dysfunctional. Here we developed a tamoxifen-inducible liver cancer mouse model with a defined oncogenic driver antigen (SV40 large T-antigen) to follow the activation and differentiation of naive tumor-specific CD8+ T (TST) cells after tumor initiation. Early during the pre-malignant phase of tumorigenesis, TST cells became dysfunctional, exhibiting phenotypic, functional, and transcriptional features similar to dysfunctional T cells isolated from late-stage human tumors. Thus, T cell dysfunction seen in advanced human cancers may already be established early during tumorigenesis. Although the TST cell dysfunctional state was initially therapeutically reversible, it ultimately evolved into a fixed state. Persistent antigen exposure rather than factors associated with the tumor microenvironment drove dysfunction. Moreover, the TST cell differentiation and dysfunction program exhibited features distinct from T cell exhaustion in chronic infections. Strategies to overcome this antigen-driven, cell-intrinsic dysfunction may be required to improve cancer immunotherapy.
Purpose: T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is a recently identified T-cell coinhibitory receptor. In this study, we aimed to determine the clinical impact of TIGIT in patients with acute myelogenous leukemia (AML) and dissect the role of TIGIT in the pathogenesis of leukemia progression.Experimental Design: TIGIT expression on T cells from peripheral blood collected from patients with AML was examined by flow cytometry. The correlation of TIGIT expression to clinical outcomes, including rate of complete remission and relapse post-allogeneic stem cell transplantation (alloSCT) in AML patients, was analyzed. Phenotypic and functional study (cytokine release, proliferation, killing, and apoptosis) of TIGIT-expressing T cells were performed. Using siRNA to silence TIGIT, we further elucidated the regulatory role of TIGIT in the T-cell immune response by dissecting the effect of TIGIT knockdown on cytokine release and apoptosis of T cells from AML patients.Results: TIGIT expression on CD8 þ T cells is elevated in AML patients and high-TIGIT correlates with primary refractory disease and leukemia relapse post-alloSCT. TIGIT þ CD8 þ T cells display phenotypic features of exhaustion and exhibit functional impairment manifested by low production of cytokines and high susceptibility to apoptosis. Importantly, their functional defects are reversed by TIGIT knockdown. Conclusions: TIGIT contributes to functional T-cell impairment and associates with poor clinical outcome in AML. Our study suggests that blockade of TIGIT to restore T-cell function and antitumor immunity may represent a novel effective leukemia therapeutic.
The cytotoxic T-lymphocyte response to wild-type simian virus 40 large tumor antigen (Tag) in C57BL/6 (H2 b ) mice is directed against three H2-D b -restricted epitopes, I, II/III, and V, and one H2-K b -restricted epitope, IV. Epitopes I, II/III, and IV are immunodominant, while epitope V is immunorecessive. We investigated whether this hierarchical response was established in vivo or was due to differential expansion in vitro by using direct enumeration of CD8 ؉ T lymphocytes with Tag epitope/major histocompatibility complex class I tetramers and intracellular gamma interferon staining. The results demonstrate that epitope IV-specific CD8 ؉ T cells dominated the Tag-specific response in vivo following immunization with full-length Tag while CD8 ؉ T cells specific for epitopes I and II/III were detected at less than one-third of this level. The immunorecessive nature of epitope V was apparent in vivo, since epitope V-specific CD8 ؉ T cells were undetectable following immunization with full-length Tag. In contrast, high levels of epitope V-specific CD8 ؉ T lymphocytes were recruited in vivo following immunization and boosting with a Tag variant in which epitopes I, II/III, and IV had been inactivated. In addition, analysis of the T-cell receptor  (TCR) repertoire of Tag epitope-specific CD8 ؉ cells revealed that multiple TCR variable regions were utilized for each epitope except Tag epitope II/III, which was limited to TCR10 usage. These results indicate that the hierarchy of Tag epitope-specific CD8 ؉ T-cell responses is established in vivo.Immunity to the large tumor antigen (Tag) of simian virus 40 (SV40) in C57BL/6 mice is characterized by the development of CD8 (23,34,50,52). An immunological hierarchy has been demonstrated among these four epitopes within Tag. Immunization of C57BL/6 mice with SV40, SV40 Tagtransformed cells, or a recombinant vaccinia virus (rVV) which encodes the full-length Tag leads to the induction of cytotoxic T lymphocytes (CTL) specific for epitopes I, II/III, and IV (26, 41, 51). Frequency estimates from limiting-dilution analysis of splenic lymphocytes obtained 9 days after immunization with SV40 Tag-transformed cells revealed that epitope IV-specific CTL represent 1 in 14,000 splenocytes while epitope I and II/III-specific CTL were less abundant (1 in 67,000) and epitope V-specific CTL were undetectable (41).Although epitope V-specific CTL are not detected following immunization with full-length SV40 Tag, immunization with syngeneic cells carrying inactivating mutations or deletions in Tag epitopes I, II/III, and IV leads to the induction of epitope V-specific CTL (41, 50). Accordingly, epitope V has been characterized as immunorecessive. Additional strategies which enhance the immunogenicity of epitope V include immunization with rVVs which express epitope V as a minigene linked to a secretory signal sequence (ES) or in which the epitope V sequence is inserted into a nonimmunogenic murine self protein, dihydrofolate reductase (26). Precise mechanisms which control the immun...
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