Search Menu
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information
Search Scholarly Publications

Title: Altered Binding of Tumor Antigenic Peptides to MHC Class I Affects CD8+ T Cell–Effector Responses

Journal Article · · Cancer Immunology Research
 [1]; ORCiD logo [2];  [1];  [1]; ORCiD logo [3];  [1]; ORCiD logo [1];  [1];  [2];  [3]
  1. Dana-Farber Cancer Institute, Boston, MA (United States)
  2. Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
  3. Dana-Farber Cancer Institute, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
+ Show Author Affiliations

T-cell priming occurs when a naïve T cell recognizes cognate peptide–MHC complexes on an activated antigen-presenting cell. The circumstances of this initial priming have ramifications on the fate of the newly primed T cell. Newly primed CD8+ T cells can embark onto different trajectories, with some becoming short-lived effector cells and others adopting a tissue resident or memory cell fate. To determine whether T-cell priming influences the quality of the effector T-cell response to tumors, here we used transnuclear CD8+ T cells that recognize the melanoma antigen TRP1 using TRP1high or TRP1low TCRs that differ in both affinity and fine specificity. From a series of altered peptide ligands, we identified a point mutation (K8) in a nonanchor residue that, when analyzed crystallographically and biophysically, destabilized the peptide interaction with the MHC binding groove. In vitro, the K8 peptide induced robust proliferation of both TRP1high and TRP1low CD8+ T cells but did not induce expression of PD-1. Cytokine production from K8-stimulated TRP1 cells was minimal, whereas cytotoxicity was increased. Upon transfer into B16 tumor–bearing mice, the reference peptide (TRP1-M9)- and K8-stimulated TRP1 cells were equally effective at controlling tumor growth but accomplished this through different mechanisms. TRP1-M9–stimulated cells produced more IFNγ, whereas K8-stimulated cells accumulated to higher numbers and were more cytotoxic. We, therefore, conclude that TCR recognition of weakly binding peptides during priming can skew the effector function of tumor-specific CD8+ T cells.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE Office of Science (SC)
OSTI ID:
1513011
Journal Information:
Cancer Immunology Research, Journal Name: Cancer Immunology Research Journal Issue: 12 Vol. 6; ISSN 2326-6066
Publisher:
American Association for Cancer Research (AACR)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (54)

Peptide-MHC class I stability is a better predictor than peptide affinity of CTL immunogenicity: Antigen processing journal June 2012
Proline substitution independently enhances H-2Dbcomplex stabilization and TCR recognition of melanoma-associated peptides journal August 2013
Db-binding peptides from influenza virus: Effect of non-anchor residues on stability and immunodominance journal June 1995
Role of non-anchor residues of Db-restricted peptides in class I binding and TCR triggering journal December 1996
A Structural Basis for LCMV Immune Evasion journal December 2002
Deconstructing the Peptide-MHC Specificity of T Cell Recognition journal May 2014
Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy journal October 2016
Low-Affinity T Cells Are Programmed to Maintain Normal Primary Responses but Are Impaired in Their Recall to Low-Affinity Ligands journal August 2013
Dependence of T Cell Antigen Recognition on T Cell Receptor-Peptide MHC Confinement Time journal February 2010
T Cell Receptor Signaling Is Limited by Docking Geometry to Peptide-Major Histocompatibility Complex journal November 2011
Mass Spectrometry Profiling of HLA-Associated Peptidomes in Mono-allelic Cells Enables More Accurate Epitope Prediction journal February 2017
Differential scanning fluorimetry based assessments of the thermal and kinetic stability of peptide–MHC complexes journal May 2016
Empty MHC class I molecules come out in the cold journal August 1990
In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target journal July 2017
Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer journal November 2017
Profiling lymphocyte interactions at the single-cell level by microfluidic cell pairing journal January 2015
T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation journal January 2008
The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability journal September 2007
Discovery of CD8 + T cell epitopes in Chlamydia trachomatis infection through use of caged class I MHC tetramers journal March 2008
T-cell receptor affinity and avidity defines antitumor response and autoimmunity in T-cell immunotherapy journal April 2013
Preemptive priming readily overcomes structure-based mechanisms of virus escape journal March 2013
Role of PD-1 during effector CD8 T cell differentiation journal April 2018
HLA-A2-peptide complexes: refolding and crystallization of molecules expressed in Escherichia coli and complexed with single antigenic peptides. journal April 1992
Binding of Viral Antigens to Major Histocompatibility Complex Class I H-2Db Molecules Is Controlled by Dominant Negative Elements at Peptide Non-anchor Residues journal July 1996
An optimized peptide vaccine strategy capable of inducing multivalent CD8+T cell responses with potent antitumor effects journal May 2015
Structural and kinetic basis for heightened immunogenicity of T cell vaccines journal April 2005
Self-reactive human CD4 T cell clones form unusual immunological synapses journal February 2012
Phaser crystallographic software journal July 2007
XDS journal January 2010
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Features and development of Coot journal March 2010
T-cell receptor binding affinities and kinetics: impact on T-cell activity and specificity journal February 2009
Different T Cell Receptor Signals Determine CD8 + Memory Versus Effector Development journal January 2009
How Antigen Quantity and Quality Determine T-Cell Decisions in Lymphoid Tissue journal April 2008
Design of Agonistic Altered Peptides for the Robust Induction of CTL Directed towards H-2Db in Complex with the Melanoma-Associated Epitope gp100 journal October 2009
Optimized Peptide Vaccines Eliciting Extensive CD8 T-Cell Responses with Therapeutic Antitumor Effects journal November 2009
Clinical Dosing Regimen of Selinexor Maintains Normal Immune Homeostasis and T-cell Effector Function in Mice: Implications for Combination with Immunotherapy journal March 2017
Getting Personal with Neoantigen-Based Therapeutic Cancer Vaccines journal July 2013
Transnuclear TRP1-Specific CD8 T Cells with High or Low Affinity TCRs Show Equivalent Antitumor Activity journal August 2013
CD4 T-cell Subsets and Tumor Immunity: The Helpful and the Not-so-Helpful journal February 2014
Cytotoxic T Lymphocytes Block Tumor Growth Both by Lytic Activity and IFNγ-Dependent Cell-Cycle Arrest journal January 2015
Vaccination with High-Affinity Epitopes Impairs Antitumor Efficacy by Increasing PD-1 Expression on CD8+ T Cells journal August 2017
Targeting Cytokine Therapy to the Pancreatic Tumor Microenvironment Using PD-L1–Specific VHHs journal April 2018
Tumor Immunity and Survival as a Function of Alternative Neopeptides in Human Cancer journal February 2018
A Single-Chain H-2Db Molecule Presenting an Influenza Virus Nucleoprotein Epitope Shows Enhanced Ability at Stimulating CD8+ T Cell Responses In Vivo journal April 2009
Human Antitumor CD8+ T Cells Producing Th1 Polycytokines Show Superior Antigen Sensitivity and Tumor Recognition journal July 2012
Structure-Based Design of Altered MHC Class II–Restricted Peptide Ligands with Heterogeneous Immunogenicity journal November 2013
Cutting Edge: The Signals for the Generation of T Cell Memory Are Qualitatively Different Depending on TCR Ligand Strength journal December 2013
Low-Affinity Memory CD8+ T Cells Mediate Robust Heterologous Immunity journal March 2016
The MHC Class I Cancer-Associated Neoepitope Trh4 Linked with Impaired Peptide Processing Induces a Unique Noncanonical TCR Conformer journal March 2016
The Immunogenicity of a Proline-Substituted Altered Peptide Ligand toward the Cancer-Associated TEIPP Neoepitope Trh4 Is Unrelated to Complex Stability journal April 2018
Cutting Edge: TCR Contacts as Anchors: Effects on Affinity and HLA-DM Stability journal December 2003
TCR Binding Kinetics Measured with MHC Class I Tetramers Reveal a Positive Selecting Peptide with Relatively High Affinity for TCR journal September 2003
Hierarchies in Cytokine Expression Profiles for Acute and Resolving Influenza Virus-Specific CD8 + T Cell Responses: Correlation of Cytokine Profile and TCR Avidity journal April 2004

Cited By (2)

Neoleukin-2 enhances anti-tumour immunity downstream of peptide vaccination targeted by an anti-MHC class II VHH journal February 2020
Neoleukin-2 enhances anti-tumour immunity downstream of peptide vaccination targeted by an anti-MHC class II VHH journal February 2020

Similar Records

Related Subjects

60 APPLIED LIFE SCIENCES
CD8+ T-cell epitopes
H-2Db
IFNg
MHC peptide binding
TRP1
cytotoxicity
melanoma self-antigen