Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma

Bonertz, Andreas; Weitz, Jürgen; Pietsch, Dong Ho Kim; Rahbari, Nuh N.; Schlude, Christoph; Ge, Yingzi; Juenger, Simone; Vlodavsky, Israël; Khazaie, Khashayarsha; Jaeger, Dirk; Reißfelder, Christoph; Antolovic, Dalibor; Aigner, Maximilian; Koch, Moritz; Beckhove, Philipp

doi:10.1172/jci39608

Cited by 151 publications

(187 citation statements)

References 56 publications

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“…We previously demonstrated that TAA-specific T reg cells in the PB of cancer patients were able to suppress polyclonally activated T cells in an Ag-specific manner. Moreover, after depleting the PBMC T cell pool of T reg cells, effector T cell responses towards some of the tested TAAs increased 29 .…”

Section: Discussionmentioning

confidence: 99%

“…T reg specificity assays were conducted similar as described elsewhere 29,30 with some necessary modifications for the transfer into the murine system. 1 × 10 4 DCs were pulsed in triplicates for each tested peptide overnight.…”

Section: Methodsmentioning

confidence: 99%

“…Our group has previously shown that TA-specific T reg cells are present in cancer patients, which can suppress the proliferation of polyclonally activated conventional T cells (T con cells) and inhibit TA-specific effector T cell responses in vitro . 29–31 The origin of TA-specific T reg cells and the extent to which natural, thymic-derived T reg cells (nT reg ) and/or induced T reg cells (iT reg ) are involved in the suppression of anti-tumor T cell responses is not clarified yet. Further, it is not well understood whether TA-specific T reg cells are solely induced and expanded by a suppressive tumor-microenvironment or possibly also by therapeutic intervention.…”

Section: Introductionmentioning

confidence: 99%

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Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

et al. 2018

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Mutated proteins arising from somatic mutations in tumors are promising targets for cancer immunotherapy. They represent true tumor-specific antigens (TSAs) as they are exclusively expressed in tumors, reduce the risk of autoimmunity and are more likely to overcome tolerance compared to wild-type (wt) sequences. Hence, we designed a panel of long peptides (LPs, 28–35 aa) comprising driver gene mutations in TP35 and KRAS frequently found in gastrointestinal tumors to test their combined immunotherapeutic potential. We found increased numbers of T cells responsive against respective mutated and wt peptides in colorectal cancer patients that carry the tested mutations in their tumors than patients with other mutations. Further, active immunization of HLA(-A2/DR1)-humanized mice with mixes of the same mutated LPs yielded simultaneous, polyvalent CD8+/CD4+ T cell responses against the majority of peptides. Peptide-specific T cells possessed a multifunctional cytokine profile with CD4+ T cells showing a TH1-like phenotype. Two mutated peptides (Kras[G12V], p53[R248W]) induced significantly higher T cell responses than corresponding wt sequences and comprised HLA-A2/DR1-restricted mutated epitopes. However, vaccination with the same highly immunogenic LPs strongly increased systemic regulatory T cells (Treg) numbers in a syngeneic sarcoma model over-expressing these mutated protein variants and resulted in accelerated tumor outgrowth. In contrast, tumor outgrowth was delayed when vaccination was directed against tumor-intrinsic Kras/Tp53 mutations of lower immunogenicity. Conclusively, we show that LP vaccination targeting multiple mutated TSAs elicits polyvalent, multifunctional, and mutation-specific effector T cells capable of targeting tumors. However, the success of this therapeutic approach can be hampered by vaccination-induced, TSA-specific Tregs.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

et al. 2018

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“…22 Although the existence of HPV16-specific regulatory T cells is reported, there is no evidence for the existence of p53-specific regulatory T cells. 22,37 However other types of regulatory T cells may have suppressed the outgrowth of p53-specific T cells. We can not exclude that the high numbers of CD4þFoxp3þ T cells detected in the tumors may have played a role.…”

Section: Discussionmentioning

confidence: 99%

Systemic and local human papillomavirus 16‐specific T‐cell immunity in patients with head and neck cancer

Heusinkveld

Goedemans

Briët

et al. 2011

Intl Journal of Cancer

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Squamous cell carcinomas of the head and neck (HNSCC), in particular those of the oropharynx, can be caused by human papilloma virus Type 16 (HPV16). Whereas these HPV-induced oropharyngeal carcinomas may express the HPV16 E6 and E7 oncoproteins and are associated with better survival, the nonvirally induced HNSCC are associated with overexpression of p53. In this study we assessed the presence of systemic and local T cells reactive against these oncoproteins in HNSCC. An exploratory study on the presence, type and function of HPV16-and/or p53-specific T cells in the blood, tumor and/or metastatic lymph node as measured by several immune assays was performed in an unselected group of 50 patients with HNSCC. Tumor tissue was tested for HPV DNA and the overexpression of p53 protein. Almost all HPV161 tumors were located in the oropharynx. Circulating HPV16-and p53-specific T cells were found in 17/47 and 7/45 tested patients. T cells were isolated from tumor cultures and/or lymph nodes of 20 patients. HPV16-specific T cells were detected in six of eight HPV1 tumors, but in none of the 12 HPV-tumors. Tumor-infiltrating p53-specific T cells were not detected. In depth analysis of the HPV16-specific T-cell response revealed that this response comprised a broad repertoire of CD41 T-helper Type 1 and 2 cells, CD41 regulatory T cells and CD81 T cells reactive to HPV16. The local presence of HPV16-specific T-cell immunity in HPV16-induced HNSCC implicates a role in the antitumor response and support the development of immunotherapy for HNSCC.

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“…Another group has successfully detected-again in melanoma patients-circulating Tregs that were specific for multiple distinct melanoma-associated antigens including the glycoprotein 100 (gp100), tyrosinase-related protein 1 (TRP1), the cancer/testis antigen NY-ESO-1 and the anti-apoptotic protein survivin [85]. A study performed in colorectal carcinoma patients has demonstrated the presence of TAAspecific Tregs and suggests that these cells may exert immunosuppressive activity over Teffs of the same specificity [86]. In line with this model, in human papillomavirus (HPV) + cervical carcinoma patients, Tregs specific for the HPV proteins E6 and E7 have been detected.…”

Section: Specificity Of Tregsmentioning

confidence: 99%

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

Tanchot

Terme

Péré

et al. 2012

Cancer Microenvironment

117

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In immunocompetent individuals, the immune system initially eradicates potentially tumorigenic cells as they develop, a capacity that is progressively lost when malignant cells acquire alterations that sustain immunosubversion and/or immunoevasion. One of the major mechanisms whereby cancer cells block antitumor immune responses involves a specific class of immunosuppressive T cells that-in the vast majority of cases-express the Forkhead box P3 (FOXP3) transcription factor. Such FOXP3 + regulatory T cells (Tregs) accumulate within neoplastic lesions as a result of several distinct mechanisms, including increased infiltration, local expansion, survival advantage and in situ development from conventional CD4 + cells.

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Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma

Abstract: Spontaneous antitumor T cell responses in cancer patients

Cited by 151 publications

References 56 publications

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

Systemic and local human papillomavirus 16‐specific T‐cell immunity in patients with head and neck cancer

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

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