Cancer Immunosurveillance by T Cells Rao, Samhita; Gharib, Karim; Han, Arnold
International review of cell and molecular biology,
2019, Volume:
342
Journal Article
Peer reviewed
Cancer immunotherapy is based on the ability of the immune system to recognize tumors as foreign tissue. The idea of cancer immunosurveillance was first conceived over a century ago but remained ...controversial through much of the 20th century. In the past few decades, however, the field has progressed rapidly, and the concept of tumor immunosurveillance is now well established. With this chapter, we provide a historical background of immunosurveillance, the concept of immunoediting, and the role of different T-cell subsets in the tumor microenvironment. We also discuss the relationship between immune checkpoints, tumor antigens, T cell receptor repertoire, and immunosurveillance. Finally, we comment on the future of immunotherapy as it relates to T cell immunosurveillance.
Although each T lymphocyte expresses a T-cell receptor (TCR) that recognizes cognate antigen and controls T-cell activation, different T cells bearing the same TCR can be functionally distinct. Each ...TCR is a heterodimer, and both α- and β-chains contribute to determining TCR antigen specificity. Here we present a methodology enabling integration of information about TCR specificity with information about T cell function. This method involves sequencing of TCRα and TCRβ genes, and amplifying functional genes characteristic of different T cell subsets, in single T cells. Because this approach retains information about individual TCRα-TCRβ pairs, TCRs of interest can be expressed and used in functional studies, for antigen discovery, or in therapeutic applications. We apply this approach to study the clonal ancestry and differentiation of T lymphocytes infiltrating a human colorectal carcinoma.
Celiac disease is an intestinal autoimmune disease driven by dietary gluten and gluten-specific CD4 ⁺ T-cell responses. In celiac patients on a gluten-free diet, exposure to gluten induces the ...appearance of gluten-specific CD4 ⁺ T cells with gut-homing potential in the peripheral blood. Here we show that gluten exposure also induces the appearance of activated, gut-homing CD8 ⁺ αβ and γδ T cells in the peripheral blood. Single-cell T-cell receptor sequence analysis indicates that both of these cell populations have highly focused T-cell receptor repertoires, indicating that their induction is antigen-driven. These results reveal a previously unappreciated role of antigen in the induction of CD8 ⁺ αβ and γδ T cells in celiac disease and demonstrate a coordinated response by all three of the major types of T cells. More broadly, these responses may parallel adaptive immune responses to viral pathogens and other systemic autoimmune diseases.
T cell receptor (TCR) sequences are very diverse, with many more possible sequence combinations than T cells in any one individual. Here we define the minimal requirements for TCR antigen ...specificity, through an analysis of TCR sequences using a panel of peptide and major histocompatibility complex (pMHC)-tetramer-sorted cells and structural data. From this analysis we developed an algorithm that we term GLIPH (grouping of lymphocyte interactions by paratope hotspots) to cluster TCRs with a high probability of sharing specificity owing to both conserved motifs and global similarity of complementarity-determining region 3 (CDR3) sequences. We show that GLIPH can reliably group TCRs of common specificity from different donors, and that conserved CDR3 motifs help to define the TCR clusters that are often contact points with the antigenic peptides. As an independent validation, we analysed 5,711 TCRβ chain sequences from reactive CD4 T cells from 22 individuals with latent Mycobacterium tuberculosis infection. We found 141 TCR specificity groups, including 16 distinct groups containing TCRs from multiple individuals. These TCR groups typically shared HLA alleles, allowing prediction of the likely HLA restriction, and a large number of M. tuberculosis T cell epitopes enabled us to identify pMHC ligands for all five of the groups tested. Mutagenesis and de novo TCR design confirmed that the GLIPH-identified motifs were critical and sufficient for shared-antigen recognition. Thus the GLIPH algorithm can analyse large numbers of TCR sequences and define TCR specificity groups shared by TCRs and individuals, which should greatly accelerate the analysis of T cell responses and expedite the identification of specific ligands.
Although T cell memory is generally thought to require direct antigen exposure, we found an abundance of memory-phenotype cells (20%–90%, averaging over 50%) of CD4+ T cells specific to viral ...antigens in adults who had never been infected. These cells express the appropriate memory markers and genes, rapidly produce cytokines, and have clonally expanded. In contrast, the same T cell receptor (TCR) specificities in newborns are almost entirely naïve, which might explain the vulnerability of young children to infections. One mechanism for this phenomenon is TCR cross-reactivity to environmental antigens, and in support of this, we found extensive cross-recognition by HIV-1 and influenza-reactive T lymphocytes to other microbial peptides and expansion of one of these after influenza vaccination. Thus, the presence of these memory-phenotype T cells has significant implications for immunity to novel pathogens, child and adult health, and the influence of pathogen-rich versus hygienic environments.
▸ Healthy adults have memory cells specific to unexposed foreign antigens ▸ Pre-existing memory-phenotype cells present in adults are absent in newborns ▸ HIV-1- and influenza-specific T cells cross-react with microbial peptides ▸ Influenza vaccination induces cross-reactive T cell expansion
The immune system can mount T cell responses against tumors; however, the antigen specificities of tumor-infiltrating lymphocytes (TILs) are not well understood. We used yeast-display libraries of ...peptide-human leukocyte antigen (pHLA) to screen for antigens of “orphan” T cell receptors (TCRs) expressed on TILs from human colorectal adenocarcinoma. Four TIL-derived TCRs exhibited strong selection for peptides presented in a highly diverse pHLA-A∗02:01 library. Three of the TIL TCRs were specific for non-mutated self-antigens, two of which were present in separate patient tumors, and shared specificity for a non-mutated self-antigen derived from U2AF2. These results show that the exposed recognition surface of MHC-bound peptides accessible to the TCR contains sufficient structural information to enable the reconstruction of sequences of peptide targets for pathogenic TCRs of unknown specificity. This finding underscores the surprising specificity of TCRs for their cognate antigens and enables the facile indentification of tumor antigens through unbiased screening.
Display omitted
•Development of a human leukocyte antigen library for TCR ligand identification•Single-cell sequencing and phenotyping of T cells infiltrating human colon cancer•Ligand discovery for four tumor-derived T cell receptors•Identification of a shared non-mutated tumor antigen between two patients
A new approach for identifying T cell receptor ligands reveals insights into the specificity of tumor-infiltrating lymphocytes.
Several cell populations have been reported to possess intestinal stem cell (ISC) activity during homeostasis and injury-induced regeneration. Here, we explored inter-relationships between putative ...mouse ISC populations by comparative RNA-sequencing (RNA-seq). The transcriptomes of multiple cycling ISC populations closely resembled Lgr5+ ISCs, the most well-defined ISC pool, but Bmi1-GFP+ cells were distinct and enriched for enteroendocrine (EE) markers, including Prox1. Prox1-GFP+ cells exhibited sustained clonogenic growth in vitro, and lineage-tracing of Prox1+ cells revealed long-lived clones during homeostasis and after radiation-induced injury in vivo. Single-cell mRNA-seq revealed two subsets of Prox1-GFP+ cells, one of which resembled mature EE cells while the other displayed low-level EE gene expression but co-expressed tuft cell markers, Lgr5 and Ascl2, reminiscent of label-retaining secretory progenitors. Our data suggest that the EE lineage, including mature EE cells, comprises a reservoir of homeostatic and injury-inducible ISCs, extending our understanding of cellular plasticity and stemness.
Display omitted
•Bmi1-GFP+ cells express mature enteroendocrine (EE) genes, including Prox1•Prox1-GFP+ and Bmi1-GFP+ cells exhibit intestinal stem cell-like clonogenic growth.•Prox1+ cells co-express EE and tuft cell genes in vivo•Lineage tracing shows that Prox1+ cells contribute to crypt homeostasis and regeneration
Multiple cell populations, represented by distinct markers including Lgr5 and Bmi1, are capable of reconstituting the intestinal epithelium. Using comparative RNA-sequencing and single-cell transcriptomics, Yan et al. define Bmi1-GFP+ and Prox1+ cells as enteroendocrine lineage cells that possess intestinal stem cell activity during homeostasis and injury-induced regeneration.
Cancer cells and embryonic tissues share a number of cellular and molecular properties, suggesting that induced pluripotent stem cells (iPSCs) may be harnessed to elicit anti-tumor responses in ...cancer vaccines. RNA sequencing revealed that human and murine iPSCs express tumor-associated antigens, and we show here a proof of principle for using irradiated iPSCs in autologous anti-tumor vaccines. In a prophylactic setting, iPSC vaccines prevent tumor growth in syngeneic murine breast cancer, mesothelioma, and melanoma models. As an adjuvant, the iPSC vaccine inhibited melanoma recurrence at the resection site and reduced metastatic tumor load, which was associated with fewer Th17 cells and increased CD11b+GR1hi myeloid cells. Adoptive transfer of T cells isolated from vaccine-treated tumor-bearing mice inhibited tumor growth in unvaccinated recipients, indicating that the iPSC vaccine promotes an antigen-specific anti-tumor T cell response. Our data suggest an easy, generalizable strategy for multiple types of cancer that could prove highly valuable in clinical immunotherapy.
Display omitted
•Irradiated iPSCs prevent tumor growth in murine models of breast, lung, and skin cancer•iPSC vaccines target shared antigens between iPSCs and cancer cells•iPSC vaccines promote a humoral and cell-mediated anti-tumor immune profile•As an adjuvant cancer therapy, iPSC vaccination can reactivate the immune system
Wu and colleagues show that cancer immunity against multiple types of cancer can be achieved using an easily generalizable iPSC-based cancer vaccine. This immunity is based on overlapping epitopes between iPSCs and cancer cells and can also be achieved by reactivating the immune system as an adjuvant immunotherapy.
Production of amphiregulin (Areg) by regulatory T (Treg) cells promotes repair after acute tissue injury. Here, we examined the function of Treg cells in non-alcoholic steatohepatitis (NASH), a ...setting of chronic liver injury. Areg-producing Treg cells were enriched in the livers of mice and humans with NASH. Deletion of Areg in Treg cells, but not in myeloid cells, reduced NASH-induced liver fibrosis. Chronic liver damage induced transcriptional changes associated with Treg cell activation. Mechanistically, Treg cell-derived Areg activated pro-fibrotic transcriptional programs in hepatic stellate cells via epidermal growth factor receptor (EGFR) signaling. Deletion of Areg in Treg cells protected mice from NASH-dependent glucose intolerance, which also was dependent on EGFR signaling on hepatic stellate cells. Areg from Treg cells promoted hepatocyte gluconeogenesis through hepatocyte detection of hepatic stellate cell-derived interleukin-6. Our findings reveal a maladaptive role for Treg cell-mediated tissue repair functions in chronic liver disease and link liver damage to NASH-dependent glucose intolerance.
Display omitted
•Treg cells are enriched and activated in human and mouse chronic liver disease•Treg cell-derived Areg promotes liver fibrosis and glucose intolerance•Areg from Treg cells activates hepatic stellate cells via EGFR signaling•Activated hepatic stellate cells promote hepatocyte gluconeogenesis via IL-6
Non-alcoholic fatty liver disease and its progressive form, non-alcoholic steatohepatitis (NASH), are a prevalent cause of chronic liver disease. Savage et al. demonstrate that regulatory T (Treg) cells are enriched in mouse and human NASH and find that production of the EGFR ligand amphiregulin by Treg cells promotes NASH-induced liver fibrosis and glucose intolerance through direct signaling to hepatic stellate cells.
In the prevailing model, Lgr5+ cells are the only intestinal stem cells (ISCs) that sustain homeostatic epithelial regeneration by upward migration of progeny through elusive upper crypt ...transit-amplifying (TA) intermediates. Here, we identify a proliferative upper crypt population marked by Fgfbp1, in the location of putative TA cells, that is transcriptionally distinct from Lgr5+ cells. Using a kinetic reporter for time-resolved fate mapping and Fgfbp1-CreERT2 lineage tracing, we establish that Fgfbp1+ cells are multi-potent and give rise to Lgr5+ cells, consistent with their ISC function. Fgfbp1+ cells also sustain epithelial regeneration following Lgr5+ cell depletion. We demonstrate that FGFBP1, produced by the upper crypt cells, is an essential factor for crypt proliferation and epithelial homeostasis. Our findings support a model in which tissue regeneration originates from upper crypt Fgfbp1+ cells that generate progeny propagating bi-directionally along the crypt-villus axis and serve as a source of Lgr5+ cells in the crypt base.
Display omitted
•Intestinal epithelial regeneration originates from the upper crypt, not the crypt base•Fgfbp1 marks upper crypt homeostatic ISCs that regenerate all lineages and Lgr5+ cells•Fgfbp1+ and Lgr5+ CBC cells exhibit differential responses to niche signals•FGFBP1 secreted by upper crypt ISCs is essential for intestinal epithelial regeneration
A revised model of the cellular hierarchy during intestinal epithelial regeneration is presented, with the identification of multi-potent intestinal stem cells in the upper crypt zone. These cells are marked by Fgfbp1 and repopulate the intestinal epithelium, including the Lgr5+ crypt base columnar cells, under homeostatic conditions.
PDF
