CD8+ T Cell Immunity Against a Tumor/Self-Antigen Is Augmented by CD4+ T Helper Cells and Hindered by Naturally Occurring T Regulatory Cells (original) (raw)
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Journal of Experimental Medicine, 2003
Many tumor-associated antigens are derived from nonmutated "self" proteins. T cells infiltrating tumor deposits recognize self-antigens presented by tumor cells and can be expanded in vivo with vaccination. These T cells exist in a functionally tolerant state, as they rarely result in tumor eradication. We found that tumor growth and lethality were unchanged in mice even after adoptive transfer of large numbers of T cells specific for an MHC class I-restricted epitope of the self/tumor antigen gp100. We sought to develop new strategies that would reverse the functionally tolerant state of self/tumor antigen-reactive T cells and enable the destruction of large (with products of perpendicular diameters of Ͼ 50 mm 2 ), subcutaneous, unmanipulated, poorly immunogenic B16 tumors that were established for up to 14 d before the start of treatment. We have defined three elements that are all strictly necessary to induce tumor regression in this model: (a) adoptive transfer of tumor-specific T cells; (b) T cell stimulation through antigen-specific vaccination with an altered peptide ligand, rather than the native self-peptide; and (c) coadministration of a T cell growth and activation factor. Cells, vaccination, or cytokine given alone or any two in combination were insufficient to induce tumor destruction. Autoimmune vitiligo was observed in mice cured of their disease. These findings illustrate that adoptive transfer of T cells and IL-2 can augment the function of a cancer vaccine. Furthermore, these data represent the first demonstration of complete cures of large, established, poorly immunogenic, unmanipulated solid tumors using T cells specific for a true self/tumor antigen and form the basis for a new approach to the treatment of patients with cancer.
The identification of many tumor-associated epitopes as nonmutated "self" Ags led to the hypothesis that the induction of large numbers of self/tumor Ag-specific T cells would be prevented because of central and peripheral tolerance. We report in this study on vaccination efforts in 95 HLA-A*0201 patients at high risk for recurrence of malignant melanoma who received prolonged immunization with the "anchor-modified" synthetic peptide, gp100 209 -217(210M) . Vaccination using this altered peptide immunogen was highly effective at inducing large numbers of self/tumor-Ag reactive T cells in virtually every patient tested, with levels as high as 42% of all CD8 ؉ T cells assessed by tetramer analysis. From 1 to 10% of all CD8 ؉ cells were tumor-Ag reactive in 44% of patients and levels >10% were generated in 17% of patients. These studies were substantiated using the ELISPOT assay and a bulk cytokine release assay. Although our data regarding "tumor escape" were inconclusive, some patients had growing tumors that expressed Ag and HLA-A*0201 in the presence of high levels of antitumor T cells. There was no difference in the levels of antitumor Ag-specific T cells in patients who recurred compared with those that remained disease-free. Thus, the mere presence of profoundly expanded numbers of vaccine-induced, self/tumor Ag-specific T cells cannot by themselves be used as a "surrogate marker" for vaccine efficacy. Further, the induction of even high levels of antitumor T cells may be insufficient to alter tumor progression.
Immunotherapy-induced CD8+ T Cells Instigate Immune Suppression in the Tumor
Molecular Therapy, 2014
Despite clear evidence of immunogenicity, cancer vaccines only provide a modest clinical benefit. To evaluate the mechanisms that limit tumor regression following vaccination, we have investigated the weak efficacy of a highly immunogenic experimental vaccine using a murine melanoma model. We discovered that the tumor adapts rapidly to the immune attack instigated by tumor-specific CD8 + T cells in the first few days following vaccination, resulting in the upregulation of a complex set of biological networks, including multiple immunosuppressive processes. This rapid adaptation acts to prevent sustained local immune attack, despite continued infiltration by increasing numbers of tumorspecific T cells. Combining vaccination with adoptive transfer of tumor-specific T cells produced complete regression of the treated tumors but did not prevent the adaptive immunosuppression. In fact, the adaptive immunosuppressive pathways were more highly induced in regressing tumors, commensurate with the enhanced level of immune attack. Examination of tumor infiltrating T-cell functionality revealed that the adaptive immunosuppression leads to a progressive loss in T-cell function, even in tumors that are regressing. These novel observations that T cells produced by therapeutic intervention can instigate a rapid adaptive immunosuppressive response within the tumor have important implications for clinical implementation of immunotherapies.
The Journal of Immunology, 2000
Although CD8 ؉ T cells play a central role as immune effectors, CD4 ؉ T cells act to control the activation and persistence of the CD8 ؉ T cell response in autoimmune disease, antiviral immunity, and experimental systems with immunogenic model tumor Ag. However, little information is available on the effects of CD4 ؉ T cells on the function of endogenous CD8 ؉ T lymphocytes recognizing authentic tumor rejection Ag with limited immunogenicity. We report here that the prophylactic or postchallenge administration of T helper Th1-type and Th2-type CD4 ؉ clones specific for an unmutated rejection Ag (murine P815AB, resembling tumor-specific shared Ag in humans) leads to the induction of P815AB-specific reactivity in vivo and concomitant tumor destruction, with quantitative rather than qualitative differences characterizing the antitumor activity of Th1 vs Th2 cells. Because the transferred CD4 ؉ cells lacked direct antitumor activity in vitro and required the de novo generation of P815AB-specific CD8 ؉ T cells in vivo, these findings suggest that CD4 ؉ lymphocytes can enhance the ability of host APC to initiate an endogenous CD8 ؉ T cell response to authentic, poorly immunogenic tumor rejection Ag.
Journal of immunology (Baltimore, Md. : 1950), 2015
Ag receptors used for cancer immunotherapy are often directed against tumor-associated Ags also expressed in normal tissues. Targeting of such Ags can result in unwanted autoimmune attack of normal tissues or induction of tolerance in therapeutic T cells. We used a murine model to study the phenotype and function of T cells redirected against the murine double minute protein 2 (MDM2), a tumor-associated Ag that shows low expression in many normal tissues. Transfer of MDM2-TCR-engineered T cells into bone marrow chimeric mice revealed that Ag recognition in hematopoietic tissues maintained T cell function, whereas presentation of MDM2 in nonhematopoietic tissues caused reduced effector function. TCR-engineered CD8(+) T cells underwent rapid turnover, downmodulated CD8 expression, and lost cytotoxic function. We found that MDM2-TCR-engineered CD4(+) T cells provided help and restored cytotoxic function of CD8(+) T cells bearing the same TCR. Although the introduction of the CD8 corece...
Tumor-specific CD4 + T cells maintain effector and memory tumor-specific CD8 + T cells
European Journal of Immunology, 2014
Immunotherapies that augment anti-tumor T cells have had recent success for treating patients with cancer. Here we examined whether tumor-specific CD4 + T cells enhance CD8 + T-cell adoptive immunotherapy in a lymphopenic environment. Our model employed physiological doses of TRP-1-CD4 + T cells and pmel-CD8 + T cells that when transferred individually were subtherapeutic; however, when transferred together provided significant (p<0.001) therapeutic efficacy. Therapeutic efficacy correlated with increased numbers of effector and memory CD8 + T cells with tumor-specific cytokine expression. When combined with CD4 + T cells, transfer of total (naïve and effector) or effector CD8 + T cells were highly effective, suggesting CD4 + T cells can help mediate therapeutic effects by maintaining function of activated CD8 + T cells. In addition, CD4 + T cells had a pronounced effect in the early post-transfer period, as their elimination within the first 3-days significantly (p<0.001) reduced therapeutic efficacy. The CD8 + T cells recovered from mice treated with both CD8 + and CD4 + T cells had decreased expression of PD-1 and PD-1-blockade enhanced the therapeutic efficacy of pmel-CD8 alone, suggesting that CD4 + T cells help reduce CD8 + Tcell exhaustion. These data support combining immunotherapies that elicit both tumorspecific CD4 + and CD8 + T cells for treatment of patients with cancer.
Concomitant Tumor Immunity to a Poorly Immunogenic Melanoma Is Prevented by Regulatory T Cells
Concomitant tumor immunity describes immune responses in a host with a progressive tumor that rejects the same tumor at a remote site. In this work, concomitant tumor immunity was investigated in mice bearing poorly immunogenic B16 melanoma. Progression of B16 tumors did not spontaneously elicit concomitant immunity. However, depletion of CD4 ϩ T cells in tumor-bearing mice resulted in CD8 ϩ T cell-mediated rejection of challenge tumors given on day 6. Concomitant immunity was also elicited by treatment with cyclophosphamide or DTA-1 monoclonal antibody against the glucocorticoid-induced tumor necrosis factor receptor. Immunity elicited by B16 melanoma cross-reacted with a distinct syngeneic melanoma, but not with nonmelanoma tumors. Furthermore, CD8 ϩ T cells from mice with concomitant immunity specifically responded to major histocompatibility complex class I-restricted epitopes of two melanocyte differentiation antigens. RAG1 ϪրϪ mice adoptively transferred with CD8 ϩ and CD4 ϩ T cells lacking the CD4 ϩ CD25 ϩ compartment mounted robust concomitant immunity, which was suppressed by readdition of CD4 ϩ CD25 ϩ cells. Naturally occurring CD4 ϩ CD25 ϩ T cells efficiently suppressed concomitant immunity mediated by previously activated CD8 ϩ T cells, demonstrating that precursor regulatory T cells in naive hosts give rise to effective suppressors. These results show that regulatory T cells are the major regulators of concomitant tumor immunity against this weakly immunogenic tumor.