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

Our plain-English summary of 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, by C. Jackaman, J.K. Gardner, F. Tomay, et al (Oncoimmunology, 2019).

The study

• Authors: C. Jackaman, J.K. Gardner, F. Tomay, J. Spowart, H. Crabb, D.E. Dye, S. Fox, S. Proksch, P. Metharom, S.S. Dhaliwal, D.J. Nelson
• Journal: Oncoimmunology
• Published: 2019;8(4):e1564452
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was an animal experiment in female C57BL/6J mice comparing young (2-3 months) and elderly (22-24 months) animals bearing AE17 mesothelioma, a cell line derived after injection of crocidolite asbestos fibres, and AE17sOVA, which expresses ovalbumin as a 'spy' tumour antigen with one dominant (SIINFEKL) and two subdominant (KVVRFDKL, NAIVFKGL) epitopes. Tumours progressed faster in elderly mice, which lost a greater percentage of body weight and had significantly elevated serum IFN-gamma, IL-6, MCP-1 and TNF-alpha. Pentamer staining showed higher proportions of CD8+ T cells specific for the dominant and the KV subdominant epitope in elderly draining lymph nodes, but an in-vivo cytotoxic T lymphocyte assay showed delayed and weaker killing of SIINFEKL-bearing targets in elderly mice, while subdominant responses were at least equal. Gemcitabine and cisplatin restrained tumour growth less well and caused more liver enzyme elevation and weight loss in elderly mice; depleting CD4+ or CD8+ T cells made tumours grow faster during chemotherapy in both ages. Gemcitabine increased KV-specific CD8+ T cells in tumours and NAIV-specific killing in draining lymph nodes in both age groups.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: animal experiment in young versus elderly mice (murine mesothelioma tumour model, with chemotherapy and T cell depletion experiments)
• Who was studied: Female C57BL/6J mice, young (2-3 months) and elderly (22-24 months), housed at Curtin University, Perth, Western Australia; group sizes ranged from 3 to 24 mice per group across experiments
• Exposure: Subcutaneous inoculation of 5 x 10^5 AE17 or AE17sOVA mesothelioma cells (AE17 derived after crocidolite asbestos injection); treatment with gemcitabine (120 micrograms/g/dose every three days) or cisplatin (6 micrograms/g/dose weekly for three doses), plus anti-CD4 or anti-CD8 depleting antibodies
• Main results:
  • Tumours grew faster in elderly mice and body weight loss relative to healthy age-matched controls was proportionally greater in elderly tumour-bearing mice
  • Serum IFN-gamma, IL-6, MCP-1 and TNF-alpha were significantly higher in elderly tumour-bearing mice than in their healthy controls and than in young healthy and tumour-bearing mice
  • Healthy elderly mice had significantly higher ALT and total protein than healthy young mice; no evidence of kidney damage was seen
  • In draining lymph nodes at day 21, the proportions of CD8+ T cells specific for the dominant SIINFEKL epitope and the subdominant KVVRFDKL epitope were significantly higher in elderly than young mice, while total CD8+ T cell proportions were lower in elderly mice
  • In the in-vivo CTL assay, SIINFEKL-specific killing in elderly mice was delayed and weak (one of three mice at day 7, four of five at day 14, all five weak but detectable at day 21), with these differences in CTL lysis not reaching statistical significance
  • Responses to the subdominant epitopes in elderly mice were at least equal to those of young mice, with KV responses in elderly draining lymph nodes emerging at day 14 and persisting to day 21
  • Depletion of CD4+ or CD8+ T cells made tumours grow faster in young mice; in elderly mice CD4+ depletion did not change tumour growth and CD8+ depletion significantly slowed tumour growth
  • Both chemotherapies restrained tumour growth significantly better in young than in elderly mice
  • Gemcitabine and cisplatin raised Alk Phos in both age groups relative to untreated tumour-bearing controls, particularly in elderly mice; elderly tumour-bearing mice also lost significantly more body weight during treatment
  • Chemotherapy efficacy in both age groups depended on T cells: with CD4+ or CD8+ T cells depleted, tumours grew faster in young and elderly mice
  • Gemcitabine reduced the proportion of SIINFEKL-specific CD8+ T cells in draining lymph nodes and tumours in both age groups and expanded KV-specific CD8+ T cells in tumours of young and elderly mice; cisplatin reduced KV-specific CD8+ T cells in elderly draining lymph nodes
  • NAIVFKGL-specific CTL activity in draining lymph nodes increased significantly with gemcitabine in both young and elderly mice
• The authors' conclusion: The authors concluded that responses to dominant tumour epitopes are functionally blunted with aging while subdominant responses remain functional and can be expanded by chemotherapy, suggesting subdominant responses may become important in elderly hosts with cancer treated with chemotherapy, although these cells still could not restrain tumour growth
• Limitations the authors state:
  • The authors note that the mechanisms behind the age-related loss of T cell function are multiple, complex and incompletely understood
  • The authors state that their supporting T cell marker data were from global T cell populations, with comparison of dominant and subdominant-specific T cells left to future studies
  • The authors note that subdominant T cell responses, and CTLs enhanced by chemotherapy, did not meaningfully slow tumour growth in elderly mice
  • For the NAIVFKGL epitope, day 7 was not analysed

Topics

Medical terms in this study, explained in our Lexicon: Chemotherapy, Life Expectancy, Mesothelioma, Cytokine, Cachexia.

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• Tumor-infiltrating dendritic cells exhibit defective cross-presentation of tumor antigens, but is reversed by chemotherapy — A.M. McDonnell, W.J. Lesterhuis, et al. (2015)
• Are macrophages, myeloid derived suppressor cells and neutrophils mediators of local suppression in healthy and cancerous tissues in aging hosts? — C. Jackaman, D.J. Nelson (2014)
• Retrospective response analysis of BAP1 expression to predict the clinical activity of systemic cytotoxic chemotherapy in mesothelioma — N. Kumar, D. Alrifai, et al. (2019)
• A Subset of Malignant Mesothelioma Tumors Retain Osteogenic Potential — S.M. Lansley, B. Pedersen, et al. (2016)

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