The Impact of Self-Tolerance on the Polyclonal CD8+ T Cell Repertoire

Kessels, Helmut W.; Visser, Karin E. de; Tirion, Felicia H.; Coccoris, Miriam; Kruisbeek, Ada M.; Schumacher, Ton N.

doi:10.4049/jimmunol.172.4.2324

Cited by 17 publications

(17 citation statements)

References 47 publications

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“…This observation implied that some level of autoreactivity is normal, confirmed later by studies on T cell tolerance [228,229]. However, the observation also pointed to an elevated level of autoreactive T cells involved in cancer.…”

Section: Introductionsupporting

confidence: 55%

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Grandics¹

2006

Mol Cancer

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This review explores similarities between lymphocytes and cancer cells, and proposes a new model for the genesis of human cancer. We suggest that the development of cancer requires infection(s) during which antigenic determinants from pathogens mimicking self-antigens are co-presented to the immune system, leading to breaking T cell tolerance. Some level of autoimmunity is normal and necessary for effective pathogen eradication. However, autoreactive T cells must be eliminated by apoptosis when the immune response is terminated. Apoptosis can be deficient in the event of a weakened immune system, the causes of which are multifactorial. Some autoreactive T cells suffer genomic damage in this process, but manage to survive. The resulting cancer stem cell still retains some functions of an inflammatory T cell, so it seeks out sites of inflammation inside the body. Due to its defective constitutive production of inflammatory cytokines and other growth factors, a stroma is built at the site of inflammation similar to the temporary stroma built during wound healing. The cancer cells grow inside this stroma, forming a tumor that provides their vascular supply and protects them from cellular immune response.As cancer stem cells have plasticity comparable to normal stem cells, interactions with surrounding normal tissues cause them to give rise to all the various types of cancers, resembling differentiated tissue types. Metastases form at an advanced stage of the disease, with the proliferation of sites of inflammation inside the body following a similar mechanism. Immunosuppressive cancer therapies inadvertently re-invigorate pathogenic microorganisms and parasitic infections common to cancer, leading to a vicious circle of infection, autoimmunity and malignancy that ultimately dooms cancer patients. Based on this new understanding, we recommend a systemic approach to the development of cancer therapies that supports rather than antagonizes the immune system.

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Section: Introductionsupporting

confidence: 55%

Untitled

Grandics¹

2006

Mol Cancer

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“…On the basis of these observations, as well as the fact that T-cell reactivity against neo-antigens should not be negatively affected by central tolerance, 9 and further, should not induce toxicity against healthy tissues, the development of vaccines that enhance neo-antigen specific T-cell reactivity is considered attractive. An important consideration in the development of such vaccines is that the majority of mutations in human tumors are ‘passengers’ that are essentially unique to individual patients.…”

Section: T-cell Immunity Directed Toward Human Tumorsmentioning

confidence: 99%

“…In this analysis, similarity to self is scored in two ways. First, the core region of a potential neo-epitope is defined as the peptide sequence between the two anchor residues and is considered to be the T-cell receptor (TCR)-exposed surface 9 , 20 . If this region is considerably different from the core-region of the parental sequence (amino acid change has a peptide:MHC binding energy covariance (PMBEC) value of ≤0.05 21 ), the mutant peptide is considered non-similar-to-self and is thus retained.…”

Section: What Is the Sensitivity Of Cancer Exome-based Neo-antigen Prmentioning

confidence: 99%

High sensitivity of cancer exome-based CD8 T cell neo-antigen identification

2014

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Recent data suggest that T-cell reactivity against tumor-specific neo-antigens may be central to the clinical efficacy of cancer immunotherapy. The development of personalized vaccines designed to boost T-cell reactivity against patient specific neo-antigens has been proposed largely on the basis of these findings. Work from several groups has demonstrated that novel tumor-specific antigens can be discovered through the use of cancer exome sequencing data, thereby providing a potential pipeline for the development of patient-specific vaccines. Importantly though, it has not been established which fraction of cancer neo-antigens that can be recognized by CD8+ T cells is successfully uncovered with the current exome-based epitope prediction strategies. Here, we use a data set comprising human cancer neo-antigens that was previously identified through the use of unbiased, computational-independent strategies to describe the potential of cancer exome-based neo-antigen discovery. This analysis shows a high sensitivity of exome-guided neo-antigen prediction of approximately 70%. We propose that future research should focus on the analysis and optimization of the specificity of neo-antigen prediction, and should undoubtedly entail the clinical evaluation of patient-specific vaccines with the aim of inducing immunoreactivity against tumor-displayed neo-antigens in a physiologically relevant context.

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“…There are experimental evidences suggesting that charge similarity is more important than subtle topographic differences between the cross-reactive complexes (Jorgensen et al, 1992;Kessels et al, 2004). However, pMHC-I complexes are 3D structures and, hence, topography variation certainly has some influence over the TCR recognition.…”

mentioning

confidence: 96%