Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis

Reißfelder, Christoph; Stamova, Slava; Gossmann, Christina; Braun, Michel Y; Bonertz, Andreas; Walliczek, Ute; Grimm, Maximilian; Rahbari, Nuh N.; Koch, Moritz; Saadati, Maral; Benner, Axel; Büchler, Markus W.; Jäger, Dirk; Halama, Niels; Khazaie, Khashayarsha; Weitz, Jürgen; Beckhove, Philipp

doi:10.1172/jci74894

Cited by 125 publications

(99 citation statements)

References 50 publications

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“…Indeed, upregulation of TNF-a expression in tumor-infiltrating T cells in colorectal cancer has been shown to correlate with an increase of intratumoral TNF-a which is indicative of tumor-specific cytotoxic activity. 49 To our knowledge, this is the first study that investigates the prognostic significance of tumor-infiltrating T cells in a fairly numerous collection of neuroblastoma patients. The information presented here might be useful in the clinical management of neuroblastoma with potential impact on patient outcome.…”

Section: Discussionmentioning

confidence: 99%

Tumor-infiltrating T lymphocytes improve clinical outcome of therapy-resistant neuroblastoma

et al. 2015

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Neuroblastoma grows within an intricate network of different cell types including epithelial, stromal and immune cells. The presence of tumor-infiltrating T cells is considered an important prognostic indicator in many cancers, but the role of these cells in neuroblastoma remains to be elucidated. Herein, we examined the relationship between the type, density and organization of infiltrating T cells and clinical outcome within a large collection of neuroblastoma samples by quantitative analysis of immunohistochemical staining. We found that infiltrating T cells have a prognostic value greater than, and independent of, the criteria currently used to stage neuroblastoma. A variable structural organization and different concurrent infiltration of T-cell subsets were detected in tumors with various outcomes. Low-risk neuroblastomas were characterized by a higher number of proliferating T cells and a more structured T-cell organization, which was gradually lost in tumors with poor prognosis. We defined an immunoscore based on the presence of CD3, CD4 and CD8 infiltrating T cells that associates with favorable clinical outcome in MYCN-amplified tumors, improving patient survival when combined with the v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) status. These findings support the hypothesis that infiltrating T cells influence the behavior of neuroblastoma and might be of clinical importance for the treatment of patients.

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Section: Discussionmentioning

confidence: 99%

Tumor-infiltrating T lymphocytes improve clinical outcome of therapy-resistant neuroblastoma

et al. 2015

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“…1 , 2 Tumor antigens (TAs) are grouped according to their tumor specificity. The first group of tumor-associated Ags (TAAs) can also be expressed by non-transformed tissue and includes over-expressed and differentiation Ags of the tissue the tumor originates from 3 , Ags resulting from abnormal posttranslational modifications 4 , and re-expressed cancer germline Ags.…”

Section: Introductionmentioning

confidence: 99%

“…2,21–25 This polyvalent T cell pool consists of effector and central T mem cells, which produce IFN-γ upon Ag re-encounter and can eliminate autologous tumor cells. 26–28 However, there is increasing evidence that tumor-associated immune suppression can be mediated in an Ag-specific manner, too.…”

Section: Introductionmentioning

confidence: 99%

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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“…(11)(12)(13)(14) CTLs can recognize antigenic peptides presented by MHC class II molecules and specifically kill tumor cells through releasing perforin and granzyme and through induction of apoptosis of tumor cells by the FasL-fas signal pathway. (11,(15)(16)(17)(18) CD4 + T cells are also important in elimination of tumor cells. CD4 + T cells can recognize antigenic peptides presented by MHC class II molecules.…”

Section: Discussionmentioning

confidence: 99%

Expression Depression ofCD300LG-γin Human Pulmonary Carcinoma

Zhai

Jiang

et al. 2016

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

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The expression of CD300LG-γ at mRNA and protein level was detected by semiquantitative reverse transcription-polymerase chain reaction (PCR), quantitative real-time PCR, and western blot, and compared by t-test analysis. The results of semiquantitative reverse transcription-PCR showed that the mRNA expression of CD300LG-γ was significantly lower in pulmonary carcinoma tissues, compared to tumor-adjacent tissues. The results of quantitative real-time PCR confirmed this finding. The mRNA level of CD300LG-γ in pulmonary carcinoma tissues compared with tumor-adjacent tissues was 0.436-fold in a median. The results of western blot indicated that CD300LG-γ protein was expressed in both pulmonary carcinoma and tumor-adjacent tissues, and the expression level was significantly lower in pulmonary carcinoma tissues compared with tumor-adjacent tissues. Both mRNA and protein levels of CD300LG-γ in pulmonary carcinoma tissues were significantly lower than that in tumor-adjacent tissues, which might lead to inhibition of killing function of immunocytes, resulting in immune escape of lung cancer cells.

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Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis

Cited by 125 publications

References 50 publications

Tumor-infiltrating T lymphocytes improve clinical outcome of therapy-resistant neuroblastoma

Tumor-infiltrating T lymphocytes improve clinical outcome of therapy-resistant neuroblastoma

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

Expression Depression ofCD300LG-γin Human Pulmonary Carcinoma

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