Viral Molecular Mimicry Influences the Antitumor Immune Response in Murine and Human Melanoma

Molecular mimicry is known to be one of the leading mechanisms by which infectious agents may induce autoimmunity. However, whether a similar mechanism triggers anti-tumor immune response is unexplored, and the role of anti-viral T-cells infiltrating the tumor has remained anecdotal. To address this question, we first developed a bioinformatic tool to identify tumor peptides with high similarity to viral epitopes. Using peptides identified by this tool, we showed that, in mice, viral pre-existing immunity enhanced the efficacy of cancer immunotherapy via molecular mimicry. Specifically, when treated with a cancer vaccine consisting of peptides with a high degree of homology with specific viral peptides, the mice with induced pre-existing immunity to these viral peptides showed significantly better anti-tumor response. To understand whether this mechanism could partly explain immunotherapy-response in humans, we analyzed a cohort of melanoma patients undergoing PD1 treatment with high IgG titer for Cytomegalovirus (CMV). In this cohort of patients, we showed that high level of CMV-antibodies was associated with a prolonged progression free survival, and found that in some cases PBMCs could cross-react with both melanoma and CMV homologous peptides. Finally, T cell TCR sequencing revealed expansion of the same CD8+ T-cell clones, when PBMCs were pulsed with tumor- or homologous viral peptides. In conclusion, we have demonstrated that pre-existing immunity and molecular mimicry could explain part of the response observed in immunotherapy. Most importantly, we have developed a tool able to identify tumor antigens and neoantigens based on their similarity to pathogen antigens, in order to exploit molecular mimicry and cross-reactive T-cells in cancer vaccine development.

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Structures suggest an approach for converting weak self-peptide tumor antigens into superagonists for CD8 T cells in cancer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2100588118 ◽

2021 ◽

Vol 118 (23) ◽

pp. e2100588118

Author(s):

Pengcheng Wei ◽

Kimberly R. Jordan ◽

Jonathan D. Buhrman ◽

Jun Lei ◽

Hexiang Deng ◽

...

Keyword(s):

T Cells ◽

Amino Acid ◽

T Cell ◽

Amino Acid Substitution ◽

Cd8 T Cells ◽

Tumor Antigens ◽

Vaccine Development ◽

Single Amino Acid ◽

Cell Repertoire ◽

Subtle Change

Tumors frequently express unmutated self-tumor–associated antigens (self-TAAs). However, trial results using self-TAAs as vaccine targets against cancer are mixed, often attributed to deletion of T cells with high-affinity receptors (TCRs) for self-TAAs during T cell development. Mutating these weak self-TAAs to produce higher affinity, effective vaccines is challenging, since the mutations may not benefit all members of the broad self-TAA–specific T cell repertoire. We previously identified a common weak murine self-TAA that we converted to a highly effective antitumor vaccine by a single amino acid substitution. In this case the modified and natural self-TAAs still raised very similar sets of CD8 T cells. Our structural studies herein show that the modification of the self-TAA resulted in a subtle change in the major histocompatibility complex I–TAA structure. This amino acid substitution allowed a dramatic conformational change in the peptide during subsequent TCR engagement, creating a large increase in TCR affinity and accounting for the efficacy of the modified self-TAA as a vaccine. These results show that carefully selected, well-characterized modifications to a poorly immunogenic self-TAA can rescue the immune response of the large repertoire of weakly responding natural self-TAA–specific CD8 T cells, driving them to proliferate and differentiate into functional effectors. Subsequently, the unmodified self-TAA on the tumor cells, while unable to drive this response, is nevertheless a sufficient target for the CD8 cytotoxic effectors. Our results suggest a pathway for more efficiently identifying variants of common self-TAAs, which could be useful in vaccine development, complementing other current nonantigen-specific immunotherapies.

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Complete Remission of Immunocytoma without Graft Versus Host Disease Caused by Allo-HLA-DP Specific T Cells.

Blood ◽

10.1182/blood.v108.11.3665.3665 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3665-3665

Author(s):

Caroline E. Rutten ◽

Simone A.P. van Luxemburg-Heijs ◽

Inge Jedema ◽

Mirjam Heemskerk ◽

Roelof Willemze ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Hematological Malignancies ◽

Class Ii ◽

Hla Class Ii ◽

Cd4 T Cell ◽

Leukemic Cells ◽

T Cell Clones ◽

Cell Clones

Abstract Mismatching for HLA-DPB1 in unrelated donor hematopoietic stem cell transplantation (URD-SCT) has been associated with a significant decreased risk of disease relapse, indicating that HLA-DP might be a target for a graft versus leukemia (GVL) effect in HLA-class II expressing hematological malignancies. To determine whether a specific GVL effect could be caused by allo-HLA-DP specific T cells, we analyzed the immune response in a patient with a refractory immunocytoma responding to donor lymphocyte infusion (DLI) after HLA-DP mismatched URD-SCT. Patient and donor were fully matched for HLA-A, -B, -C, -DR and -DQ, but differed for both HLA-DP alleles (donor HLA-DPB1*0402/0501; patient HLA-DPB*020102/0301). The patient received a T cell depleted URD-SCT after a non-myeloablative conditioning regimen, resulting in mixed chimerism (75% donor) without GVHD. Because of a hematological relapse, a single DLI was given 6 months after SCT, resulting in a profound anti-leukemic effect with only grade I GVHD, treated with topical corticosteroids. 6 weeks after DLI, malignant cells in peripheral blood (PB) had dropped from 72% to 47%. 7 weeks later, only 3% malignant cells were present, and after 4 months, complete remission and conversion to full donor chimerism in the absence of GVHD was observed. To determine whether allo-HLA-DP specific T cells were involved in the immune response, leukemia-reactive donor T cell clones were isolated from PB or bone marrow at different time points during the response to DLI. Patient derived T cells were overnight stimulated with irradiated leukemic cells harvested before transplantation, and clonal IFNγ producing T cells were sorted and expanded. 21 CD4+ T cell clones, 19 CD8+ T cell clones and 6 NK cell clones were tested for recognition of patient or donor derived cells as measured by IFNγ production and cytotoxic activity. The CD8+ or NK clones did not recognize patient leukemic cells. However, all 21 CD4+ clones produced INFγ in response to patient leukemic cells but not to donor cells. To determine whether these CD4+ T cell clones were capable of killing the leukemic cells, a CFSE based cytotoxicity assay was performed. 8 clones showed 30–90% lysis of the leukemic cell population. To further analyze the specificity of these CD4+ clones, blocking and panel studies were performed. Blocking with the HLA-DP specific mAb B7.21 abrogated IFNγ production by all clones, confirming HLA-DP restricted recognition. A panel study using 12 unrelated EBV-LCL expressing different HLA-DP alleles identified 18 clones specific for HLA-DPB1*0301, and 3 clones specific for HLA-DPB1*0201. To analyze the polyclonality of the immune response, the distribution of TCR Vβ chains was characterized by RT-PCR and sequence reactions. 7 different Vβs were found within the HLA-DPB1*0301 specific clones and 3 different Vβs within the HLA-DPB1*0201 specific clones. T cells using the same Vβ could be isolated at different time points during the clinical response, demonstrating the significance of this anti-HLA-DP response. In conclusion, we observed in a patient with an HLA-class II positive B cell malignancy a profound GVL effect without GVHD, caused by a polyclonal immune response comprising both T helper and cytotoxic CD4+ HLA-DP specific T cell clones directed against both HLA-DP alleles. These data indicate that in HLA-class II expressing hematological malignancies HLA-DP mismatched SCT may be preferable over a fully matched SCT making use of HLA-DP as a specific target for immunotherapy.

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Melanocyte Destruction after Antigen-Specific Immunotherapy of Melanoma

Journal of Experimental Medicine ◽

10.1084/jem.192.11.1637 ◽

2000 ◽

Vol 192 (11) ◽

pp. 1637-1644 ◽

Cited By ~ 322

Author(s):

Cassian Yee ◽

John A. Thompson ◽

Patrick Roche ◽

David R. Byrd ◽

Peter P. Lee ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Specific Immunotherapy ◽

Tumor Antigens ◽

Normal Tissues ◽

Cell Clones ◽

Expression Evidence ◽

Tumor Biopsies

Current strategies for the immunotherapy of melanoma include augmentation of the immune response to tumor antigens represented by melanosomal proteins such as tyrosinase, gp100, and MART-1. The possibility that intentional targeting of tumor antigens representing normal proteins can result in autoimmune toxicity has been postulated but never demonstrated previously in humans. In this study, we describe a patient with metastatic melanoma who developed inflammatory lesions circumscribing pigmented areas of skin after an infusion of MART-1–specific CD8+ T cell clones. Analysis of the infiltrating lymphocytes in skin and tumor biopsies using T cell–specific peptide–major histocompatibility complex tetramers demonstrated a localized predominance of MART-1–specific CD8+ T cells (>28% of all CD8 T cells) that was identical to the infused clones (as confirmed by sequencing of the complementarity-determining region 3). In contrast to skin biopsies obtained from the patient before T cell infusion, postinfusion biopsies demonstrated loss of MART-1 expression, evidence of melanocyte damage, and the complete absence of melanocytes in affected regions of the skin. This study provides, for the first time, direct evidence in humans that antigen-specific immunotherapy can target not only antigen-positive tumor cells in vivo but also normal tissues expressing the shared tumor antigen.

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Selective Depletion of High-Avidity Human Immunodeficiency Virus Type 1 (HIV-1)-Specific CD8+ T Cells after Early HIV-1 Infection

Journal of Virology ◽

10.1128/jvi.01388-06 ◽

2007 ◽

Vol 81 (8) ◽

pp. 4199-4214 ◽

Cited By ~ 88

Author(s):

Mathias Lichterfeld ◽

Xu G. Yu ◽

Stanley K. Mui ◽

Katie L. Williams ◽

Alicja Trocha ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Chronic Infection ◽

Early Infection ◽

High Avidity ◽

Cell Clones ◽

Immunodeficiency Virus ◽

High Level ◽

Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells in early infection are associated with the dramatic decline of peak viremia, whereas their antiviral activity in chronic infection is less apparent. The functional properties accounting for the antiviral activity of HIV-1-specific CD8+ T cells during early infection are unclear. Using cytokine secretion and tetramer decay assays, we demonstrated in intraindividual comparisons that the functional avidity of HIV-1-specific CD8+ T cells was consistently higher in early infection than in chronic infection in the presence of high-level viral replication. This change of HIV-1-specific CD8+ T-cell avidity between early and chronic infections was linked to a substantial switch in the clonotypic composition of epitope-specific CD8+ T cells, resulting from the preferential loss of high-avidity CD8+ T-cell clones. In contrast, the maintenance of the initially recruited clonotypic pattern of HIV-1-specific CD8+ T cells was associated with low-level set point HIV-1 viremia. These data suggest that high-avidity HIV-1-specific CD8+ T-cell clones are recruited during early infection but are subsequently lost in the presence of persistent high-level viral replication.

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Magnitude and Dynamics of the T-Cell Response to SARS-CoV-2 Infection at Both Individual and Population Levels

10.1101/2020.07.31.20165647 ◽

2020 ◽

Cited By ~ 14

Author(s):

Thomas M Snyder ◽

Rachel M Gittelman ◽

Mark Klinger ◽

Damon H May ◽

Edward J Osborne ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Cell Response ◽

Vaccine Development ◽

Human Leukocyte ◽

Cd8 T Cell ◽

T Cell Response ◽

Clinical Diagnostics ◽

Cell Repertoire

T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection. Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides (class II data in a forthcoming study). Then, at the population level, we performed T-cell repertoire sequencing on 1,815 samples (from 1,521 COVID-19 subjects) as well as 3,500 controls to identify shared "public" T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells. Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for at least several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3-7 = 85.1% [95% CI = 79.9-89.7]; Day 8-14 = 94.8% [90.7-98.4]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 95.4% [92.1-98.3]). These results demonstrate an approach to reliably assess the adaptive immune response both soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points. This blood-based molecular approach to characterizing the cellular immune response has applications in clinical diagnostics as well as in vaccine development and monitoring.

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Selecting Target Antigens for Cancer Vaccine Development

Vaccines ◽

10.3390/vaccines8040615 ◽

2020 ◽

Vol 8 (4) ◽

pp. 615 ◽

Cited By ~ 3

Author(s):

Luigi Buonaguro ◽

Maria Tagliamonte

Keyword(s):

T Cell ◽

Cancer Vaccine ◽

Cancer Vaccines ◽

Tumor Antigens ◽

Vaccine Development ◽

T Cell Response ◽

Therapeutic Cancer Vaccine ◽

Memory T Cell ◽

Heteroclitic Peptides ◽

Therapeutic Cancer Vaccines

One of the principal goals of cancer immunotherapy is the development of efficient therapeutic cancer vaccines that are able to elicit an effector as well as memory T cell response specific to tumor antigens. In recent years, the attention has been focused on the personalization of cancer vaccines. However, the efficacy of therapeutic cancer vaccines is still disappointing despite the large number of vaccine strategies targeting different tumors that have been evaluated in recent years. While the preclinical data have frequently shown encouraging results, clinical trials have not provided satisfactory data to date. The main reason for such failures is the complexity of identifying specific target tumor antigens that should be unique or overexpressed only by the tumor cells compared to normal cells. Most of the tumor antigens included in cancer vaccines are non-mutated overexpressed self-antigens, eliciting mainly T cells with low-affinity T cell receptors (TCR) unable to mediate an effective anti-tumor response. In this review, the target tumor antigens employed in recent years in the development of therapeutic cancer vaccine strategies are described, along with potential new classes of tumor antigens such as the human endogenous retroviral elements (HERVs), unconventional antigens, and/or heteroclitic peptides.

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Longitudinal high-throughput TCR repertoire profiling reveals the dynamics of T cell memory formation after mild COVID-19 infection

10.1101/2020.05.18.100545 ◽

2020 ◽

Cited By ~ 6

Author(s):

Anastasia A. Minervina ◽

Ekaterina A. Komech ◽

Aleksei Titov ◽

Meriem Bensouda Koraichi ◽

Elisa Rosati ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

High Throughput ◽

T Cell Response ◽

Immune Memory ◽

Antigen Specificity ◽

Antiviral Immune Response ◽

T Cell Clones ◽

Cell Clones

COVID-19 is a global pandemic caused by the SARS-CoV-2 coronavirus. T cells play a key role in the adaptive antiviral immune response by killing infected cells and facilitating the selection of virus-specific antibodies. However neither the dynamics and cross-reactivity of the SARS-CoV-2-specific T cell response nor the diversity of resulting immune memory are well understood. In this study we use longitudinal high-throughput T cell receptor (TCR) sequencing to track changes in the T cell repertoire following two mild cases of COVID-19. In both donors we identified CD4+ and CD8+ T cell clones with transient clonal expansion after infection. The antigen specificity of CD8+ TCR sequences to SARS-CoV-2 epitopes was confirmed by both MHC tetramer binding and presence in large database of SARS-CoV-2 epitope-specific TCRs. We describe characteristic motifs in TCR sequences of COVID-19-reactive clones and show preferential occurence of these motifs in publicly available large dataset of repertoires from COVID-19 patients. We show that in both donors the majority of infection-reactive clonotypes acquire memory phenotypes. Certain T cell clones were detected in the memory fraction at the pre-infection timepoint, suggesting participation of pre-existing cross-reactive memory T cells in the immune response to SARS-CoV-2.

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Revealing factors determining immunodominant responses against dominant epitopes

Immunogenetics ◽

10.1007/s00251-019-01134-9 ◽

2019 ◽

Vol 72 (1-2) ◽

pp. 109-118 ◽

Cited By ~ 4

Author(s):

Wannisa Ritmahan ◽

Can Kesmir ◽

Renske M.A. Vroomans

Keyword(s):

Immune Response ◽

T Cells ◽

Amino Acid ◽

T Cell ◽

Influenza A ◽

Viral Infections ◽

Cell Clone ◽

Amino Acid Sequences ◽

Cell Clones ◽

T Cell Clone

AbstractUpon recognition of peptide-MHC complexes by T cell receptors (TCR), the cognate T cells expand and differentiate into effector T cells to generate protective immunity. Despite the fact that any immune response generates a diverse set of TCR clones against a particular epitope, only a few clones are highly expanded in any immune response. Previous studies observed that the highest frequency clones usually control viral infections better than subdominant clones, but the reasons for this dominance among T cell clones are still unclear. Here, we used publicly available TCR amino acid sequences to study which factors determine whether a response becomes immunodominance (ID) per donor; we classified the largest T cell clone as the epitope-specific dominant clone and all the other clones as subdominant responses (SD). We observed a distinctively hydrophobic CDR3 in ID responses against a dominant epitope from influenza A virus, compared to the SD responses. The common V-J combinations were shared between ID and SD responses, suggesting that the biased V-J recombination events are restricted by epitope specificity; thus, the immunodominance is not directly determined by a bias combination of V and J genetic segments. Our findings reveal a close similarity of global sequence properties between dominant and subdominant clones of epitope-specific responses but detectable distinctive amino acid enrichments in ID. Taken together, we believe this first comparative study of immunodominant and subdominant TCR sequences can guide further studies to resolve factors determining the immunodominance of antiviral as well as tumor-specific T cell responses.

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The Human Vaccines Project: A roadmap for cancer vaccine development

Science Translational Medicine ◽

10.1126/scitranslmed.aaf0685 ◽

2016 ◽

Vol 8 (334) ◽

pp. 334ps9-334ps9 ◽

Cited By ~ 85

Author(s):

Pedro Romero ◽

Jacques Banchereau ◽

Nina Bhardwaj ◽

Mark Cockett ◽

Mary L. Disis ◽

...

Keyword(s):

Immune Response ◽

Clinical Efficacy ◽

Cancer Vaccine ◽

Cancer Vaccines ◽

Tumor Antigens ◽

Vaccine Development ◽

Antitumor Immune Response ◽

International Effort

Cancer vaccine development has been vigorously pursued for 40 years. Immunity to tumor antigens can be elicited by most vaccines tested, but their clinical efficacy remains modest. We argue that a concerted international effort is necessary to understand the human antitumor immune response and achieve clinically effective cancer vaccines.

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IL-7 and IL-15 differentially regulate CD8+ T-cell subsets during contraction of the immune response

Blood ◽

10.1182/blood-2008-06-160945 ◽

2008 ◽

Vol 112 (9) ◽

pp. 3704-3712 ◽

Cited By ~ 106

Author(s):

Mark P. Rubinstein ◽

Nicholas A. Lind ◽

Jared F. Purton ◽

Pauline Filippou ◽

J. Adam Best ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Interleukin 7 ◽

High Level ◽

Cd127 Expression

Although it is known that interleukin-7 (IL-7) and IL-15 influence the survival and turnover of CD8+ T cells, less is known about how these cytokines affect different subsets during the course of the immune response. We find that IL-7 and IL-15 differentially regulate CD8+ T-cell subsets defined by KLRG1 and CD127 expression during the contraction phase of the immune response. The provision of IL-15, or the related cytokine IL-2, during contraction led to the preferential accumulation of KLRG1hiCD127lo CD8+ T cells, whereas provision of IL-7 instead favored the accumulation of KLRG1loCD127hi cells. While IL-7 and IL-15 both induced proliferation of KLRG1lo cells, KLRG1hi cells exhibited an extraordinarily high level of resistance to cytokine-driven proliferation in vivo despite their dramatic accumulation upon IL-15 administration. These results suggest that IL-15 and IL-2 greatly improve the survival of KLRG1hi CD8+ T cells, which are usually destined to perish during contraction, without inducing proliferation. As the availability of IL-15 and IL-2 is enhanced during periods of extended inflammation, our results suggest a mechanism in which a population of cytokine-dependent KLRG1hi CD8+ T cells is temporarily retained for improved immunity. Consideration of these findings may aid in the development of immunotherapeutic strategies against infectious disease and cancer.

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