scholarly journals Human Tumor Antigens and Cancer Immunotherapy

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Nathalie Vigneron
Keyword(s):  
T Cells ◽  
Turning Point ◽  
Tumor Antigens ◽  
Human Tumor ◽  
Immune Checkpoints ◽  
Antigenic Peptides ◽  
Cytolytic T Lymphocytes ◽  
Cell Therapies ◽  
Key Players ◽  
Recent Developments

With the recent developments of adoptive T cell therapies and the use of new monoclonal antibodies against the immune checkpoints, immunotherapy is at a turning point. Key players for the success of these therapies are the cytolytic T lymphocytes, which are a subset of T cells able to recognize and kill tumor cells. Here, I review the nature of the antigenic peptides recognized by these T cells and the processes involved in their presentation. I discuss the importance of understanding how each antigenic peptide is processed in the context of immunotherapy and vaccine delivery.

CMV-Specific T-Cells Are More Effective Than WT-1-Specific T-Cells in Eradicating Clonogenic Tumor Cells Co-Expressing CMVpp65 and WT-1 in-Vivo and Both Types of T-Cells Are Functionally Augmented in the Presence of IL-15/IL-15Rα

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 646-646 ◽  
Author(s):  
Aisha Hasan ◽  
Dana Bakalar ◽  
Annamalai Selvakumar ◽  
Gloria C Koo ◽  
Ekaterina Doubrovina ◽  
...  
Keyword(s):  
T Cells ◽  
Ovarian Carcinoma ◽  
Tumor Cells ◽  
Tumor Antigen ◽  
Tumor Antigens ◽  
Human Tumor ◽  
Relative Efficacy ◽  
Comparative Efficacy ◽  
Anti Tumor Activity

Abstract Abstract 646 Adoptively transferred virus or tumor antigen-specific T-cells have demonstrated efficacy in initial clinical trials, but while clearance of viral infection is sustained, responses to tumor-specific T-cells are usually short-lived. Therefore, current efforts are focused on distinguishing attributes of virus-specific T-cells that contribute to their persistence and formulating strategies to sustain anti-tumor effects of T-cell (TC) therapies. We have developed an in-vivo model to compare the relative efficacy of T-cells specific for a tumor antigen (WT-1) versus T-cells specific for a viral antigen (CMVpp65) using human colon carcinoma cells that express the oncofetal protein WT-1 which were transduced to co-express CMVpp65 (WT-1[+] cocapp65) as a surrogate system. Groups of 6 NOD/Scid-IL2Rgc-KO/J mice (NSG) were each subcutaneously injected with 3 × 105 WT-1 [+] cocapp65 on the R flank. Each animal was also injected with 3 × 105 cells from a WT-1[+] ovarian carcinoma cell line (SKOV3-A2) on the L shoulder to compare the efficacy of WT-1 specific T-cells (WT1-CTLs) against different WT-1 [+] tumor cell types. Expression of WT-1 protein is lower in SKOV3-A2 than in cocapp65 cells. Both tumors are HLA A0201[+] and were transduced to express a GFP-firefly luciferase gene. T-cells were administered intravenously 5 days after tumor injection to enable vascularization and tumor growth was quantitated using bioluminescence. These experiments evaluated (1) the relative capacity of CMVpp65 specific T-cells (CMV-CTLs) versus WT-1 CTLs to eradicate WT1[+] cocapp65 cells that co-express a viral and tumor antigen (2) the relative efficacy of WT-1 CTLs against 2 different HLA A0201 [+] WT-1 expressing tumors; an ovarian carcinoma and a colon carcinoma, and (3) the contribution of IL-15/15Rα complex in augmenting the efficacy of antigen specific T-cells by using intraperitoneally (i.p) injected Baf-3 cells transduced to express human IL-15/15Rα complex. The treatment groups were as follows: (1) Control – no T-cells + IL-2 (2000 U) (2) Control – no T-cells + IL-15/IL-15Rα (5 × 106 baf-3 cells) (3) WT1 CTLs + IL-2 (2000 U) (4) CMV-CTLs + IL-2 (2000 U) (5) WT1 CTLs + IL-15/IL-15Rα (5 × 106 baf-3 cells) (6) CMV-CTLs + IL-15/IL-15Rα (5 × 106 baf-3 cells). IL-2 and irradiated baf-3 cells were administered intraperitoneally twice weekly. When the doses of antigen specific interferon gamma (IFNg) [+] T-cells were equivalent in the infused CMVpp65 and WT1 specific T-cells, the CMV-CTLs induced greater, and more sustained suppression of the growth of the WT-1[+] cocapp65 cells in-vivo than the WT-1 CTLs (Fig.1). The anti-tumor activity of the WT-1 CTLs was greater against WT-1[+] cocapp65 than against the WT-1[+] ovarian carcinoma (SKOV3-A2), potentially reflecting the higher expression of WT-1 in cocapp65. The SKOV3-A2 tumor began to re-grow by 24 days post T-cell infusion approaching the size of control tumors by day 38, while the WT-1[+] cocapp65 still demonstrated slower growth through day 38. The addition of IL-15/15Rα increased the efficacy of the transferred T-cells, the difference being more pronounced for the anti-tumor activity of WT-1 CTLs. Fig. 1 Comparative Efficacy of CMV and WT-1 CTLs against Human Tumor Targets Co-expressing CMVpp65 and WT-1 Fig. 1. Comparative Efficacy of CMV and WT-1 CTLs against Human Tumor Targets Co-expressing CMVpp65 and WT-1 These studies demonstrate that equivalent doses of IFNg[+] WT-1 CTLs can also suppress WT-1[+] cocapp65 tumor xenografts, but are less effective than CMV-CTLs, and that IL-15 supplementation augments the cytotoxic activity of the CTLs in-vitro and enhances the duration of the anti-tumor effects in-vivo. This model permits side by side comparisons of the anti-tumor activity of human T-cells directed against viral and tumor antigens expressed on the same clonogenic human tumor target. Because both responses are directed against the same cells, this model could thereby facilitate identification of the distinguishing features of T-cells specific for viral or tumor antigens as well as differences in the presentation of viral and oncofetal “self” antigens by tumor cells that contribute to disparities in their anti-tumor activity and persistence in-vivo. Disclosures: No relevant conflicts of interest to declare.

Immune profiling of tumor-infiltrating T cells using mass cytometry.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2607-2607
Author(s):  
David Roumanes ◽  
Evan Newell ◽  
Michael Fehlings
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Antigens ◽  
Human Cancer ◽  
Human Tumor ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Subsets ◽  
High Dimensional ◽  
Tumor Bearing ◽  
Immune Profiling

2607 Background: Immunotherapy recent successes have opened new avenues for the treatment of cancer and the presence of tumor-specific CD8+ T cells in tumor-bearing individuals offer a promising therapeutic target. However, the detection and profiling of such T cells are challenging due to the need to detect rare antigen-specific T cell subpopulations in patient samples that are limited in size thus making it difficult to exploit these parameters for predictive signatures of clinical response. Moreover, the identification and analysis of neoantigen-specific CD8+ T-cells in tumor-bearing individuals is challenging due to the small pool of such cells. Methods: In order to identify therapy-relevant tumor antigens and to facilitate a concurrent in-depth characterization of cells directed towards these targets, immunoSCAPE leverages the high-dimensional immune profiling capabilities of cytometry by time of flight (CyTOF) combined with a unique technology allowing the identification rare antigen-specific T-cell subsets. Results: We applied this technology to patient tumor-infiltrating lymphocytes from human cancer samples and tumor-derived neoantigens recognized by T-cells were identified and characterized. Interestingly, the majority of patient-derived tumor infiltrates consisted of tumor-unrelated T-cells characterized by a diverse phenotype. Strikingly, the expression of CD39 was absent from these bystander cells, suggesting that CD39 could be a useful biomarker for the identification of putative tumor-reactive T cells. Conclusions: Simultaneous immune profiling revealed that tumor-unrelated, bystander CD8+ T-cells are phenotypically different in human tumor infiltrates and identified CD39 as a putative marker of neoantigen-specific T-cells. By providing insights into the nature, frequency and phenotype of antigen-specific T-cells, immunoSCAPE’s unique target discovery and high-dimensional immune profiling platform is a valuable tool for the development of novel diagnostic and therapeutic strategies in immunotherapy.

A listing of human tumor antigens recognized by T cells: March 2004 update

2004 ◽  
Vol 54 (3) ◽  
pp. 187-207 ◽  
Author(s):  
Luisa Novellino ◽  
Chiara Castelli ◽  
Giorgio Parmiani
Keyword(s):  
T Cells ◽  
Tumor Antigens ◽  
Human Tumor

scholarly journals Immune Checkpoints and CAR-T Cells: The Pioneers in Future Cancer Therapies?

2020 ◽  
Vol 21 (21) ◽  
pp. 8305
Author(s):  
Negar Hosseinkhani ◽  
Afshin Derakhshani ◽  
Omid Kooshkaki ◽  
Mahdi Abdoli Shadbad ◽  
Khalil Hajiasgharzadeh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Side Effects ◽  
Immune Responses ◽  
Gene Editing ◽  
Tumor Antigens ◽  
Immune Checkpoints ◽  
Car T Cells ◽  
Ample Opportunity ◽  
Car T

Although the ever-increasing number of cancer patients pose substantial challenges worldwide, finding a treatment with the highest response rate and the lowest number of side effects is still undergoing research. Compared to chemotherapy, the relatively low side effects of cancer immunotherapy have provided ample opportunity for immunotherapy to become a promising approach for patients with malignancy. However, the clinical translation of immune-based therapies requires robust anti-tumoral immune responses. Immune checkpoints have substantial roles in the induction of an immunosuppressive tumor microenvironment and tolerance against tumor antigens. Identifying and targeting these inhibitory axes, which can be established between tumor cells and tumor-infiltrating lymphocytes, can facilitate the development of anti-tumoral immune responses. Bispecific T-cell engagers, which can attract lymphocytes to the tumor microenvironment, have also paved the road for immunological-based tumor elimination. The development of CAR-T cells and their gene editing have brought ample opportunity to recognize tumor antigens, independent from immune checkpoints and the major histocompatibility complex (MHC). Indeed, there have been remarkable advances in developing various CAR-T cells to target tumoral cells. Knockout of immune checkpoints via gene editing in CAR-T cells might be designated for a breakthrough for patients with malignancy. In the midst of this fast progress in cancer immunotherapies, there is a need to provide up-to-date information regarding immune checkpoints, bispecific T-cell engagers, and CAR-T cells. Therefore, this review aims to provide recent findings of immune checkpoints, bispecific T-cell engagers, and CAR-T cells in cancer immunotherapy and discuss the pertained clinical trials.

scholarly journals Identification of a Mutated Fibronectin As a Tumor Antigen Recognized by CD4+T Cells

2002 ◽  
Vol 195 (11) ◽  
pp. 1397-1406 ◽  
Author(s):  
Helen Y. Wang ◽  
Juhua Zhou ◽  
Kuichun Zhu ◽  
Adam I. Riker ◽  
Francesco M. Marincola ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Tumor Antigen ◽  
Cd4 T Cells ◽  
Tumor Antigens ◽  
Cell Epitope ◽  
Human Tumor ◽  
Metastatic Potential ◽  
Sequencing Analysis ◽  
Tumor Cell Migration

CD4+ T cells play an important role in orchestrating host immune responses against cancer, particularly by providing critical help for priming and extending the survival of CD8+ T cells. However, relatively little is known about major histocompatibility complex class II–restricted human tumor antigens capable of activating CD4+ T cells. Here, we describe the identification of a mutated fibronectin (FN) as a tumor antigen recognized by human histocompatibility leukocyte antigen-DR2–restricted CD4+ T cells. Deoxyribonucleic acid (DNA) sequencing analysis indicated that this gene contains a mutation that results in the substitution of lysine for glutamic acid and gives rise to a new T cell epitope recognized by CD4+ T cells. Tumor cells harboring the mutant FN resulted in the loss of FN matrix formation and the gain of metastatic potential based on the migration pattern compared with that of tumor cells that express wild-type FN. Additional experiments using cell lines stably expressing the mutated FN cDNA demonstrated that the point mutation in FN was responsible for the loss of FN staining in extracellular matrices and the enhancement of tumor cell migration. These findings represent the first demonstration that a mutated gene product recognized by CD4+ T cells is directly involved in tumor metastasis, which indicates the importance of CD4+ T cells in controlling the spread of tumor cells to distant anatomic sites.

scholarly journals Human regulatory T cells at the maternal-fetal interface show functional site-specific adaptation with tumor-infiltrating-like features

2019 ◽  
Author(s):  
Judith Wienke ◽  
Laura Brouwers ◽  
Leone van der Burg ◽  
Michal Mokry ◽  
Rianne C. Scholman ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Human Tumor ◽  
Control Site ◽  
Transcriptional Profile ◽  
Functional Adaptation ◽  
Immune Checkpoints ◽  
Site Specific ◽  
Transcriptional Signature ◽  
Maternal Fetal Interface

AbstractObjectivesRegulatory T cells (Tregs) are crucial for maintaining immune tolerance against the semi-allogeneic fetus during pregnancy. Since their functional profile at the human maternal-fetal interface is still elusive, we investigated the transcriptional profile and functional adaptation of human uterine Tregs (uTregs) during pregnancy.MethodsBlood and uterine biopsies from the placental bed (=maternal-fetal interface) and incision site (=control), were obtained from women with uneventful pregnancies undergoing primary Caesarean section. Tregs and CD4+ non-Tregs (Tconv) were isolated for transcriptomic profiling by Cel-Seq2. Results were validated on protein and single cell level by flow cytometry.ResultsPlacental bed uterine Tregs (uTregs) showed elevated expression of Treg signature markers compared to blood Tregs, including FOXP3, CTLA4 and TIGIT. The uTreg transcriptional profile was indicative of late-stage effector Treg differentiation and chronic activation with high expression of immune checkpoints GITR, TNFR2, OX-40, 4-1BB, genes associated with suppressive capacity (CTLA4, HAVCR2, IL10, IL2RA, LAYN, PDCD1), activation (HLA-DR, LRRC32), and transcription factors MAF, PRDM1, BATF, and VDR. uTregs mirrored uTconv Th1 polarization, and characteristics indicating tissue-residency, including high CD69, CCR1, and CXCR6. The particular transcriptional signature of placental bed uTregs overlapped strongly with the specialized profile of human tumor-infiltrating Tregs, and, remarkably, was more pronounced at the placental bed than uterine control site.ConclusionuTregs at the maternal-fetal interface acquire a highly differentiated effector Treg profile similar to tumor-infiltrating Tregs, which is locally enriched compared to a distant uterine site. This introduces the novel concept of site-specific transcriptional adaptation of human Tregs within one organ.

scholarly journals Development of Human Neuroblastomas in Mouse-Human Neural Crest Chimeras

2019 ◽  
Author(s):  
Malkiel A. Cohen ◽  
Shupei Zhang ◽  
Satyaki Sengupta ◽  
Haiting Ma ◽  
Brendan Horton ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Neural Crest ◽  
Human Cancer ◽  
Cytotoxic T Cells ◽  
Human Tumor ◽  
Model System ◽  
Mouse Embryos ◽  
Immune Checkpoints ◽  
Experimental Platform

SummaryNeuroblastoma (NB), derived from the neural crest (NC), is the most common pediatric extracranial solid tumor. Here we establish a platform that allows studying human NBs in mouse-human NC chimeras. Chimeric mice were produced by injecting human NC cells carrying NB relevant oncogenes in-utero into gastrulating mouse embryos. The mice developed tumors composed of a heterogenous cell population that closely resembled that seen in primary NBs of patients but were significantly different from homogenous tumors formed in xenotransplantation models. The human tumors emerged in immunocompetent hosts and were extensively infiltrated by mouse cytotoxic T cells reflecting a vigorous host anti-tumor immune response. However, the tumors blunted the immune response by inducing infiltration of regulatory T cells and expression of immune checkpoints similar to escape mechanisms seen in human cancer patients. Thus, this experimental platform allows studying human tumor initiation, progression, manifestation and tumor – immune-system interactions in an animal model system.

scholarly journals Inefficient ZAP70-Signaling Blunts Antigen Detection by CAR-T-Cells

2019 ◽  
Author(s):  
Venugopal Gudipati ◽  
Julian Rydzek ◽  
Iago Doel Perez ◽  
Lydia Scharf ◽  
Sebastian Königsberger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Molecule ◽  
Rational Design ◽  
Tumor Antigens ◽  
Immunological Synapse ◽  
Detailed Knowledge ◽  
Cell Therapies ◽  
Car T Cells ◽  
Car T

ABSTRACTRational design of chimeric antigen receptors (CARs) with optimized anti-cancer performance mandates detailed knowledge of how CARs engage tumor antigens and how antigen-engagement triggers activation. We analyzed CAR-mediated antigen recognition via quantitative single molecule live-cell imaging and found the sensitivity of CAR-T-cells towards antigen approximately 1000-times reduced when compared to T-cell antigen receptor (TCR)-mediated recognition of nominal peptide/MHC complexes. While CARs outperformed TCRs with regard to antigen binding within the immunological synapse, proximal signaling was significantly attenuated due to inefficient recruitment of the tyrosine-kinase ZAP70 to ligated CARs and its reduced concomitant activation and subsequent release. Our study exposes signaling deficiencies of state-of-the-art CAR-designs, which limit at present the efficacy of CAR-T-cell therapies to target tumors with diminished antigen expression.

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