Minimal Tolerance to a Tumor Antigen Encoded by a Cancer-Germline Gene

Huijbers, Ivo J.; Soudja, Saïdi M.; Uyttenhove, Catherine; Buferne, Michel; Inderberg, Else Marit; Colau, Didier; Pilotte, Luc; Tenbossche, Céline G. Powis de; Chomez, Patrick; Brasseur, Francis; Schmitt-Verhulst, Anne-Marie; Eynde, Benoı̂t J. Van den

doi:10.4049/jimmunol.1002612

Cited by 26 publications

(25 citation statements)

References 43 publications

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“…However, P1A-deficient mice demonstrated enhanced P1A-specific T cell responses and increased tumor protection from P1A-expressing P815 tumor cells. Furthermore, TCR-Vβ usage of P1A-specific T cells was slightly altered, suggesting that ectopic expression of P1A during thymic development skews the peripheral T cell repertoire [55]. These results and others support a role for central tolerance in limiting, not eliminating, T cell responses against self-antigens [56, 57].…”

Section: Central Tolerancementioning

confidence: 72%

“…Mice deficient in gp70 are more resistant to CT26 tumor challenge, and their CD8+ T cells following immunization with the AH1 peptide display increased staining intensity with the AH1-H-2L d multimers, suggestive of a higher avidity T cell response [54]. Huijbers et al [55] recently demonstrated similar results using the non-mutated cancer–testis antigen P1A from the mastocytoma tumor P815. Functional CD8+ T cell responses following vaccination with the H-2L d -restricted P1A 35–43 epitope are detectable in DBA/2 mice that express P1A in the thymus, suggesting incomplete central tolerance to this antigen.…”

Section: Central Tolerancementioning

confidence: 95%

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Improving T cell responses to modified peptides in tumor vaccines

Buhrman

Slansky

2012

Immunol Res

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Immune recognition and elimination of cancerous cells is the primary goal of cancer immunotherapy. However, obstacles including immune tolerance and tumor-induced immunosuppression often limit beneficial immune responses. Vaccination is one proposed intervention that may help to overcome these issues and is an active area of study in cancer immunotherapy. Immunizing with tumor antigenic peptides is a promising, straight-forward vaccine strategy hypothesized to boost preexisting antitumor immunity. However, tumor antigens are often weak T cell agonists, attributable to several mechanisms, including immune self-tolerance and poor immunogenicity of self-derived tumor peptides. One strategy for overcoming these mechanisms is vaccination with mimotopes, or peptide mimics of tumor antigens, which alter the antigen presentation and/or T cell activation to increase the expansion of tumor-specific T cells. Evaluation of mimotope vaccine strategies has revealed that even subtle alterations in peptide sequence can dramatically alter antigen presentation and T cell receptor recognition. Most of this research has been performed using T cell clones, which may not be accurate representations of the naturally occurring antitumor response. The relationship between clones generated after mimotope vaccination and the polyclonal T cell repertoire is unclear. Our work with mimotopes in a mouse model of colon carcinoma has revealed important insights into these issues. We propose that the identification of mimotopes based on stimulation of the naturally responding T cell repertoire will dramatically improve the efficacy of mimotope vaccination.

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Section: Central Tolerancementioning

confidence: 72%

Section: Central Tolerancementioning

confidence: 95%

Improving T cell responses to modified peptides in tumor vaccines

Buhrman

Slansky

2012

Immunol Res

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“…We have specifically focused on SSX2, which we found is expressed in ~25% of metastatic prostate cancer lesions [18], and immune responses to which we have observed in patients with prostate cancer [14,17]. As a CTA this protein likely has limited central tolerance since its expression in normal tissues is restricted to immune-privileged testis tissue [19]. We previously identified two HLA-A2-restricted SSX2 epitopes (p41–49 and p103–111), T cells specific for which can lyse SSX2-expressing prostate cancer cells, and we demonstrated that HLA-A2 transgenic mice immunized with a DNA vaccine encoding SSX2 develop p41–49- and p103–111-specific T cells [17,18].…”

Section: Introductionmentioning

confidence: 99%

DNA vaccines encoding altered peptide ligands for SSX2 enhance epitope-specific CD8+ T-cell immune responses

Smith

Rekoske

McNeel

2014

Vaccine

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Plasmid DNA serves as a simple and easily modifiable form of antigen delivery for vaccines. The USDA approval of DNA vaccines for several non-human diseases underscores the potential of this type of antigen delivery method as a cost-effective approach for the treatment or prevention of human diseases, including cancer. However, while DNA vaccines have demonstrated safety and immunological effect in early phase clinical trials, they have not consistently elicited robust anti-tumor responses. Hence many recent efforts have sought to increase the immunological efficacy of DNA vaccines, and we have specifically evaluated several target antigens encoded by DNA vaccine as treatments for human prostate cancer. In particular, we have focused on SSX2 as one potential target antigen, given its frequent expression in metastatic prostate cancer. We have previously identified two peptides, p41–49 and p103–111, as HLA-A2-restricted SSX2-specific epitopes. In the present study we sought to determine whether the efficacy of a DNA vaccine could be enhanced by an altered peptide ligand (APL) strategy wherein modifications were made to anchor residues of these epitopes to enhance or ablate their binding to HLA-A2. A DNA vaccine encoding APL modified to increase epitope binding elicited robust peptide-specific CD8+ T cells producing Th1 cytokines specific for each epitope. Ablation of one epitope in a DNA vaccine did not enhance immune responses to the other epitope. These results demonstrate that APL encoded by a DNA vaccine can be used to elicit increased numbers of antigen-specific T cells specific for multiple epitopes simultaneously, and suggest this could be a general approach to improve the immunogenicity of DNA vaccines encoding tumor antigens.

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“…Additionally, Aire deficient mice may have increased memory response to melanoma following immunization with irradiated melanoma cells (19). At the same time, however, recent work also suggests that thymic expression of a cancer-germline antigen only minimally changes T cell responses to antigen-expressing tumors (20). Additionally, Aire-regulated thymic expression of tyrosinase, a shared vitiligo/melanoma antigen, does not shape the tyrosinase-specific T cell repertoire (21).…”

Section: Introductionmentioning

confidence: 99%

Aire Deficiency Promotes TRP-1–Specific Immune Rejection of Melanoma

Zhu

Nagavalli

2013

Cancer Research

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The thymic transcription factor AIRE prevents autoimmunity in part by promoting expression of tissue-specific self-antigens, which include many cancer antigens. For example, AIRE-deficient patients are predisposed to vitiligo, an autoimmune disease of melanocytes that is often triggered by efficacious immunotherapies against melanoma. Therefore, we hypothesized that Aire deficiency in mice may elevate immune responses to cancer and provide insights into how such responses might be triggered. In this study, we show that Aire deficiency decreases thymic expression of TRP-1 (TYRP1), which is a self-antigen in melanocytes and a cancer antigen in melanomas. Aire deficiency resulted in defective negative selection of TRP-1 specific T cells without affecting thymic numbers of regulatory T cells. Aire deficient mice displayed elevated T cell immune responses that were associated with suppression of melanoma outgrowth. Further, transplantation of Aire-deficient thymic stroma was sufficient to confer more effective immune rejection of melanoma in an otherwise Aire wildtype host. Together, our work showed how Aire deficiency can enhance immune responses against melanoma, and how manipulating TRP-1 specific T cell negative selection may offer a logical strategy to enhance immune rejection of melanoma.

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Minimal Tolerance to a Tumor Antigen Encoded by a Cancer-Germline Gene

Cited by 26 publications

References 43 publications

Improving T cell responses to modified peptides in tumor vaccines

Improving T cell responses to modified peptides in tumor vaccines

DNA vaccines encoding altered peptide ligands for SSX2 enhance epitope-specific CD8+ T-cell immune responses

Aire Deficiency Promotes TRP-1–Specific Immune Rejection of Melanoma

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