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

Connie Jackaman, Joanne K. Gardner, Federica Tomay, Joshua Spowart, Hannah Crabb, Danielle E. Dye, Simon Fox, Stephen Proksch, Pat Metharom, Satvinder S. Dhaliwal, Delia J. Nelson

Research output: Contribution to journalArticle

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.

Original languageEnglish
Number of pages17
JournalOncoImmunology
DOIs
Publication statusE-pub ahead of print - 17 Jan 2019
Externally publishedYes

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Neoplasm Antigens
T-Lymphocytes
Drug Therapy
Epitopes
Neoplasms
Cachexia
Poisons
Mesothelioma
Ovalbumin
Cytotoxic T-Lymphocytes
Life Expectancy
Immune System
Vaccination
Lymph Nodes
Staining and Labeling
Cytokines
Incidence

Cite this

Jackaman, Connie ; Gardner, Joanne K. ; Tomay, Federica ; Spowart, Joshua ; Crabb, Hannah ; Dye, Danielle E. ; Fox, Simon ; Proksch, Stephen ; Metharom, Pat ; Dhaliwal, Satvinder S. ; Nelson, Delia J. / 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. In: OncoImmunology. 2019.
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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.",
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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. / Jackaman, Connie; Gardner, Joanne K.; Tomay, Federica; Spowart, Joshua; Crabb, Hannah; Dye, Danielle E.; Fox, Simon; Proksch, Stephen; Metharom, Pat; Dhaliwal, Satvinder S.; Nelson, Delia J.

In: OncoImmunology, 17.01.2019.

Research output: Contribution to journalArticle

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AU - Jackaman, Connie

AU - Gardner, Joanne K.

AU - Tomay, Federica

AU - Spowart, Joshua

AU - Crabb, Hannah

AU - Dye, Danielle E.

AU - Fox, Simon

AU - Proksch, Stephen

AU - Metharom, Pat

AU - Dhaliwal, Satvinder S.

AU - Nelson, Delia J.

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N2 - 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.

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KW - hierarchical T cell responses

KW - mesothelioma

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