Online citations, reference lists, and bibliographies.
← Back to Search

CD8+ Cytotoxic T Cell Responses To Dominant Tumor-associated Antigens Are Profoundly Weakened By Aging Yet Subdominant Responses Retain Functionality And Expand In Response To Chemotherapy

C. Jackaman, Joanne K Gardner, F. Tomay, J. Spowart, H. Crabb, D. Dye, S. Fox, Stephen Proksch, P. Metharom, S. Dhaliwal, D. Nelson
Published 2019 · Medicine

Cite This
Download PDF
Analyze on Scholarcy
Share
ABSTRACT Increasing life expectancy is associated with increased cancer incidence, yet the effect of cancer and anti-cancer treatment on elderly patients and their immune systems is not well understood. Declining T cell function with aging in response to infection and vaccination is well documented, however little is known about aged T cell responses to tumor antigens during cancer progression or how these responses are modulated by standard chemotherapy. We examined T cell responses to cancer in aged mice using AE17sOVA mesothelioma in which ovalbumin (OVA) becomes a ‘spy’ tumor antigen containing one dominant (SIINFEKL) and two subdominant (KVVRFDKL and NAIVFKGL) epitopes. Faster progressing tumors in elderly (22–24 months, cf. 60–70 human years) relative to young (2–3 months, human 15–18 years) mice were associated with increased pro-inflammatory cytokines and worsened cancer cachexia. Pentamer staining and an in-vivo cytotoxic T lymphocyte (CTL) assay showed that whilst elderly mice generated a greater number of CD8+ T cells recognizing all epitopes, they exhibited a profound loss of function in their ability to lyse targets expressing the dominant, but not subdominant, epitopes compared to young mice. Chemotherapy was less effective and more toxic in elderly mice however, similar to young mice, chemotherapy expanded CTLs recognizing at least one subdominant epitope in tumors and draining lymph nodes, yet treatment efficacy still required CD8+ T cells. Given the significant dysfunction associated with elderly CTLs recognizing dominant epitopes, our data suggest that responses to subdominant tumor epitopes may become important when elderly hosts with cancer are treated with chemotherapy.
This paper references
10.1371/journal.pone.0041112
High Avidity Cytotoxic T Lymphocytes Can Be Selected into the Memory Pool but They Are Exquisitely Sensitive to Functional Impairment
V. Brentville (2012)
10.1200/JCO.2002.06.171
Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines.
M. Disis (2002)
10.4049/jimmunol.165.11.6123
In Vivo Cross-Presentation of a Soluble Protein Antigen: Kinetics, Distribution, and Generation of Effector CTL Recognizing Dominant and Subdominant Epitopes1
D. Nelson (2000)
10.18356/02911eeb-en
[World population prospects].
A. Parant (1990)
10.1016/j.arr.2017.07.002
Modulation of dendritic cell and T cell cross-talk during aging: The potential role of checkpoint inhibitory molecules
Joanne K Gardner (2017)
10.1158/0008-5472.CAN-12-1123
High-avidity T cells are preferentially tolerized in the tumor microenvironment.
Ziqiang Zhu (2013)
10.1016/j.aogh.2016.01.019
The Global Health Dimensions of Asbestos and Asbestos-Related Diseases.
K. Takahashi (2016)
10.18632/ONCOTARGET.4414
Distinctive clinical characteristics of malignant mesothelioma in young patients
A. Thomas (2015)
10.1111/j.1474-9726.2010.00611.x
Partial restoration of T‐cell function in aged mice by in vitro blockade of the PD‐1/ PD‐L1 pathway
C. S. Lages (2010)
10.1007/s10522-009-9260-0
Delayed but excellent myogenic stem cell response of regenerating geriatric skeletal muscles in mice
T. Shavlakadze (2009)
10.1016/j.humimm.2013.01.015
Analyses of T cell-mediated immune response to a human melanoma-associated antigen by the young and the elderly.
N. Chakraborty (2013)
10.1084/jem.20160636
Preventing tumor escape by targeting a post-proteasomal trimming independent epitope
Ana Textor (2016)
Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors.
A. Nowak (2003)
10.1038/sj.bjc.6605329
Vaccination with Mage-b DNA induces CD8 T-cell responses at young but not old age in mice with metastatic breast cancer
F. Castro (2009)
10.1183/09031936.00000811
Predicting survival in malignant mesothelioma
A. Musk (2011)
10.1371/journal.ppat.1003129
Kinetics of Antigen Expression and Epitope Presentation during Virus Infection
N. Croft (2013)
10.1016/j.lfs.2015.10.025
Men and mice: Relating their ages.
S. Dutta (2016)
10.4049/jimmunol.181.3.2124
Naive Precursor Frequencies and MHC Binding Rather Than the Degree of Epitope Diversity Shape CD8+ T Cell Immunodominance1
Maya F. Kotturi (2008)
10.1126/stke.112pt2
In Vivo Imaging of T Cell Priming
S. E. Henrickson (2008)
10.1007/s00262-009-0687-6
The effect of aging on OX40 agonist-mediated cancer immunotherapy
Carl E. Ruby (2009)
10.1111/acel.12435
Characterization of age‐associated exhausted CD8+ T cells defined by increased expression of Tim‐3 and PD‐1
Kyoo‐A Lee (2016)
10.1007/s00262-008-0636-9
Mechanisms of murine dendritic cell antitumor dysfunction in aging
Annabelle Grolleau-Julius (2008)
10.1136/oemed-2017-104298
Estimation of the global burden of mesothelioma deaths from incomplete national mortality data
Chimed-Ochir Odgerel (2017)
10.1158/1078-0432.CCR-05-0185
Role of Mononuclear Cells and Inflammatory Cytokines in Pancreatic Cancer-Related Cachexia
M. Martignoni (2005)
10.1371/journal.pone.0020838
Plasmacytoid DC from Aged Mice Down-Regulate CD8 T Cell Responses by Inhibiting cDC Maturation after Encephalitozoon cuniculi Infection
J. Gigley (2011)
10.2486/INDHEALTH.45.379
Malignant mesothelioma: global incidence and relationship with asbestos.
C. Bianchi (2007)
10.1182/blood-2015-02-626754
Mechanisms of PD-L1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eµ-TCL1 CLL mouse model.
F. McClanahan (2015)
10.4049/jimmunol.171.10.5051
IL-2 Intratumoral Immunotherapy Enhances CD8+ T Cells That Mediate Destruction of Tumor Cells and Tumor-Associated Vasculature: A Novel Mechanism for IL-2 1
C. Jackaman (2003)
Recognition of multiple epitopes in the human melanoma antigen gp100 by tumor-infiltrating T lymphocytes associated with in vivo tumor regression.
Y. Kawakami (1995)
10.1038/bjc.2014.312
Prognostic factors in elderly patients with malignant pleural mesothelioma: results of a multicenter survey
G. Ceresoli (2014)
10.1006/VIRO.1998.9148
Role of a subdominant H-2Kd-restricted SV40 tumor antigen cytotoxic T lymphocyte epitope in tumor rejection.
R. Newmaster (1998)
10.1111/imm.12477
Autologous cellular vaccine overcomes cancer immunoediting in a mouse model of myeloma
M. Mazzocco (2015)
10.1111/j.0105-2896.2005.00259.x
The role of CD8+ T‐cell replicative senescence in human aging
Rita B. Effros (2005)
10.1016/j.arr.2010.09.008
Impact of age on T cell signaling: A general defect or specific alterations?
A. Larbi (2011)
10.1172/JCI20945
IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin.
E. Nemeth (2004)
10.1093/gerona/glu057
Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases.
C. Franceschi (2014)
10.1111/j.1749-6632.2009.05370.x
Potential role of immunosenescence in cancer development
T. Fulop (2010)
10.1016/j.lungcan.2015.05.014
Treatment patterns and survival analysis in 9014 patients with malignant pleural mesothelioma from Belgium, the Netherlands and England.
R. Damhuis (2015)
10.3389/fimmu.2018.01538
A Mechanistic Model for Predicting Cell Surface Presentation of Competing Peptides by MHC Class I Molecules
D. Boulanger (2018)
Immunodominance inmajor histocompatibility complex class I-restricted T lymphocyte responses
JW Yewdell (1999)
10.1146/ANNUREV.IMMUNOL.17.1.51
Immunodominance in major histocompatibility complex class I-restricted T lymphocyte responses.
J. Yewdell (1999)
10.1111/jgs.13523
Comparative Effectiveness of Chemotherapy Regimens in Prolonging Survival for Two Large Population‐Based Cohorts of Elderly Adults with Breast and Colon Cancer in 1992–2009
X. Du (2015)
10.1038/s41598-017-02088-2
Cancer cachexia associates with a systemic autophagy-inducing activity mimicked by cancer cell-derived IL-6 trans-signaling
Kristine Pettersen (2017)
10.1371/journal.ppat.1002544
Early Priming Minimizes the Age-Related Immune Compromise of CD8+ T Cell Diversity and Function
S. Valkenburg (2012)
10.1007/s00262-013-1489-4
HER-2/neu vaccine-primed autologous T-cell infusions for the treatment of advanced stage HER-2/neu expressing cancers
M. Disis (2013)
10.1016/S0264-410X(02)00530-3
Low effectiveness of DNA vaccination against HER-2/neu in ageing.
M. Provinciali (2003)
10.1007/s00262-012-1307-4
Chemotherapy broadens the range of tumor antigens seen by cytotoxic CD8+ T cells in vivo
C. Jackaman (2012)
10.1002/EJI.1830250935
Cytotoxic T lymphocytes raised against a subdominant epitope offered as a synthetic peptide eradicate human papillomavirus type 16‐induced tumors
Mariet C. W. Feltkamp (1995)



This paper is referenced by
Semantic Scholar Logo Some data provided by SemanticScholar