Multiepitope CD8+ T cell response to a NY-ESO-1 peptide vaccine results in imprecise tumor targeting

BackgroundThe majority of JAK2V617F-negative myeloproliferative neoplasms (MPN) have disease-initiating frameshift mutations in calreticulin (CALR) resulting in a common novel C-terminal mutant fragment (CALRMUT), representing an attractive source of neoantigens for cancer vaccines. However, studies have shown that CALRMUT-specific T cells are rare in CALRMUT MPN patients, but the underlying reasons for this phenomenon are unknown.MethodsIn this study, we examine class-I major histocompatibility complex (MHC-I) allele frequency in CALRMUT MPN patients from two independent cohorts and observed that MHC-I alleles that present CALRMUT neoepitopes with high affinity are under-represented in CALRMUT MPN patients. We speculate that this is due to an increased chance of immune-mediated tumor rejection by individuals expressing one of these MHC-I alleles such that the disease never clinically manifests. As a consequence of this MHC-I allele restriction, we reasoned that CALRMUT MPN patients would not efficiently respond to cancer vaccines composed of the CALRMUT fragment, but could do so when immunized with a properly modified CALRMUT heteroclitic peptide vaccine approach.ResultsWe found that heteroclitic CALRMUT peptides specifically designed for CALRMUT MPN patient MHC-I alleles efficiently elicited a cross-reactive CD8+ T cell response in human PBMC samples otherwise unable to respond to the matched weakly immunogenic CALRMUT native peptides. We also modeled this effect in mice and observed that C57BL/6J mice, which are unable to mount an immune response to the human CALRMUT fragment, can mount a cross-reactive CD8+ T cell response against a CALRMUT-derived peptide upon heteroclitic peptide immunization and this was further amplified by combining the heteroclitic peptide vaccine with blockade of the immune checkpoint molecule PD-1.ConclusionsTogether, our data underscore the therapeutic potential of heteroclitic peptide-based cancer vaccines in CALRMUT MPN patients.Ethics ApprovalApproval was obtained for the use of patient-derived specimens and access to clinical data extracted from patient charts by the Institutional Review Boards at Memorial Sloan Kettering Cancer Center, the Dana-Farber Cancer Institute and the Massachusetts General Hospital, as well as by the Danish Regional Science Ethics Committee. Mouse experiments were performed in accordance with institutional guidelines under a protocol approved by the Memorial Sloan-Kettering Cancer Center Institutional Animal Care and Use Committee.

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Liver damage dampens anti-viral CD8 T cell response by inducing loss of surface T cell receptor expression

10.1055/s-0038-1677266 ◽

2019 ◽

Author(s):

V König ◽

K Manske ◽

S Kurz ◽

K Steiger ◽

PA Knolle ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Liver Damage ◽

Cell Response ◽

Cd8 T Cell ◽

Cell Receptor ◽

T Cell Response ◽

Receptor Expression

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Faculty Opinions recommendation of Dendritic cells maximize the memory CD8 T cell response to infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1025997.321895 ◽

2005 ◽

Author(s):

David Woodland

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response ◽

Memory Cd8 T Cell

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Faculty Opinions recommendation of Transcriptional insights into the CD8(+) T cell response to infection and memory T cell formation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717977293.793476883 ◽

2013 ◽

Author(s):

Donna Farber ◽

Naomi Yudanin

Keyword(s):

T Cell ◽

Cell Response ◽

Cell Formation ◽

Cd8 T Cell ◽

T Cell Response ◽

Memory T Cell

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Faculty Opinions recommendation of Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718880272.793524108 ◽

2016 ◽

Author(s):

Michael Postow

Keyword(s):

T Cell ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response

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An epidemic Zika virus isolate suppresses antiviral immunity by disrupting antigen presentation pathways

Nature Communications ◽

10.1038/s41467-021-24340-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ryan D. Pardy ◽

Stefanie F. Valbon ◽

Brendan Cordeiro ◽

Connie M. Krawczyk ◽

Martin J. Richer

Keyword(s):

T Cell ◽

Zika Virus ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response ◽

Cross Presentation ◽

Cell Immunity ◽

Asian Lineage ◽

Insight Into ◽

Host Tissues

AbstractZika virus (ZIKV) has emerged as an important global health threat, with the recently acquired capacity to cause severe neurological symptoms and to persist within host tissues. We previously demonstrated that an early Asian lineage ZIKV isolate induces a highly activated CD8 T cell response specific for an immunodominant epitope in the ZIKV envelope protein in wild-type mice. Here we show that a contemporary ZIKV isolate from the Brazilian outbreak severely limits CD8 T cell immunity in mice and blocks generation of the immunodominant CD8 T cell response. This is associated with a more sustained infection that is cleared between 7- and 14-days post-infection. Mechanistically, we demonstrate that infection with the Brazilian ZIKV isolate reduces the cross-presentation capacity of dendritic cells and fails to fully activate the immunoproteasome. Thus, our study provides an isolate-specific mechanism of host immune evasion by one Brazilian ZIKV isolate, which differs from the early Asian lineage isolate and provides potential insight into viral persistence associated with recent ZIKV outbreaks.

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Nano-Microparticle Platforms in Developing Next-Generation Vaccines

Vaccines ◽

10.3390/vaccines9060606 ◽

2021 ◽

Vol 9 (6) ◽

pp. 606

Author(s):

Giuseppe Cappellano ◽

Hugo Abreu ◽

Chiara Casale ◽

Umberto Dianzani ◽

Annalisa Chiocchetti

Keyword(s):

Immune Response ◽

T Cell ◽

Cell Response ◽

Humoral Response ◽

Cd8 T Cell ◽

T Cell Response ◽

Next Generation ◽

Emerging Viruses ◽

Whole Cells ◽

Effector Functions

The first vaccines ever made were based on live-attenuated or inactivated pathogens, either whole cells or fragments. Although these vaccines required the co-administration of antigens with adjuvants to induce a strong humoral response, they could only elicit a poor CD8+ T-cell response. In contrast, next-generation nano/microparticle-based vaccines offer several advantages over traditional ones because they can induce a more potent CD8+ T-cell response and, at the same time, are ideal carriers for proteins, adjuvants, and nucleic acids. The fact that these nanocarriers can be loaded with molecules able to modulate the immune response by inducing different effector functions and regulatory activities makes them ideal tools for inverse vaccination, whose goal is to shut down the immune response in autoimmune diseases. Poly (lactic-co-glycolic acid) (PLGA) and liposomes are biocompatible materials approved by the Food and Drug Administration (FDA) for clinical use and are, therefore, suitable for nanoparticle-based vaccines. Recently, another candidate platform for innovative vaccines based on extracellular vesicles (EVs) has been shown to efficiently co-deliver antigens and adjuvants. This review will discuss the potential use of PLGA-NPs, liposomes, and EVs as carriers of peptides, adjuvants, mRNA, and DNA for the development of next-generation vaccines against endemic and emerging viruses in light of the recent COVID-19 pandemic.

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