The Regulatory Status Adopted by Lymph Node Dendritic Cells and T Cells During Healthy Aging Is Maintained During Cancer and May Contribute to Reduced Responses to Immunotherapy

Our plain-English summary of The Regulatory Status Adopted by Lymph Node Dendritic Cells and T Cells During Healthy Aging Is Maintained During Cancer and May Contribute to Reduced Responses to Immunotherapy, by J.K. Gardner, C. Jackaman, C.D.S. Mamotte, et al (Frontiers in Medicine, 2018).

The study

• Authors: J.K. Gardner, C. Jackaman, C.D.S. Mamotte, D.J. Nelson
• Journal: Frontiers in Medicine
• Published: 2018;5:337
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Aging is associated with an increased incidence of cancer. One contributing factor could be modulation of immune cells responsible for anti-tumor responses, such as dendritic cells (DCs) and T cells. These immunological changes may also impact the efficacy of cancer immunotherapies in the elderly. The effects of healthy aging on DCs and T cells, and their impact on anti-mesothelioma immune responses, had not been reported. This study examined DCs and T cells in young (2-5 months; equivalent to 16-26 human years) and elderly (20-24 months; equivalent to 60-70 human years) healthy and mesothelioma-bearing C57BL/6J mice. During healthy aging, elderly lymph nodes adopted a regulatory profile, characterized by: (i) increased plasmacytoid DCs, (ii) increased expression of the adenosine-producing enzyme CD73 on CD11c+ cells, and (iii) increased expression of multiple regulatory markers (including CD73, the adenosine A2B receptor, CTLA-4, PD-1, ICOS, LAG-3, and IL-10) on CD8+ and CD4+ T cells, compared to lymph nodes from young mice. Although mesotheliomas grew faster in elderly mice, the increased regulatory status observed in healthy elderly lymph node DCs and T cells was not further exacerbated. However, elderly tumor-bearing mice demonstrated reduced MHC-I, MHC-II and CD80 on CD11c+ cells, and decreased IFN-γ by CD8+ and CD4+ T cells within tumors, compared to young counterparts, implying loss of function. An agonist CD40 antibody based immunotherapy was less efficient at promoting tumor regression in elderly mice, which may be due to: (i) failure of elderly CD8+ T cells to up-regulate perforin, and (ii) increased expression of multiple regulatory markers on CD11c+ cells and T cells in elderly tumor-draining lymph nodes (including CD73, PD-1, ICOS, LAG-3, and TGF-β). Our findings suggest that checkpoint blockade may improve responses to immunotherapy in elderly hosts with mesothelioma, and warrants further investigation.

In plain English

This was a laboratory study in female C57BL/6J mice. It compared young mice (2 to 5 months old, which the authors equate to 16 to 26 human years) with elderly mice (20 to 24 months, equated to 60 to 70 human years). Some mice were injected under the skin with AE17 mesothelioma cells. This mouse cell line was originally derived from mice injected with asbestos; the study mice received tumor cells, not asbestos. The authors measured immune cells (dendritic cells and T cells) in lymph nodes and tumors. In healthy elderly mice, lymph nodes showed more immune-suppressing (regulatory) markers than in young mice. When tumors were present, this pattern remained but was not made worse. Tumors grew faster in elderly mice. A treatment combining interleukin-2 with an anti-CD40 antibody produced tumor regression in 45% of treated elderly mice versus 100% of treated young mice. Tumor-specific killing by T cells was lower in elderly mice, both treated and untreated. The authors concluded that adding checkpoint blockade might improve this treatment in elderly hosts with mesothelioma. They said further study after a full treatment schedule is needed.

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 comparing young and elderly mice, healthy and tumor-bearing, with and without IL-2/anti-CD40 immunotherapy; immune cells measured by flow cytometry
• Who was studied: Female C57BL/6J mice from the Animal Resources Center, Western Australia: young (2 to 5 months) and elderly (20 to 24 months), housed at Curtin University; group sizes varied by experiment (for example 13 young and 15 elderly in the tumor growth experiment)
• Exposure: Subcutaneous injection of 5 x 10^5 AE17 (or ovalbumin-marked AE17sOVA) mesothelioma cells. AE17 is a cell line derived from mice injected with asbestos; no fiber type is named. Some tumor-bearing mice were treated inside the tumor with IL-2 (20 micrograms per dose) plus agonist anti-CD40 antibody (40 micrograms per dose), or with PBS diluent, every 2 to 3 days for 5 doses.
• Main results:
  • AE17 mesothelioma tumors grew faster in elderly mice than in young mice (13 young and 15 elderly mice inoculated)
  • In healthy mice, elderly lymph nodes showed a regulatory profile compared with young lymph nodes: more plasmacytoid dendritic cells, more CD73 on CD11c+ dendritic cells, and multiple regulatory markers on T cells
  • In tumor-bearing mice, the presence of a tumor did not alter the age-related increases in regulatory markers on elderly lymph node T cells
  • Within tumors of elderly mice compared with young mice, CD11c+ cells had significantly reduced MHC-II and CD80, with a non-significant trend for reduced MHC-I (p = 0.08)
  • In elderly tumors compared with young tumors, CD8+ and CD4+ T cells showed reduced IFN-gamma
  • A full 5-dose course of IL-2/anti-CD40 produced tumor regression in 45% of elderly mice compared with 100% of young mice; the figure legend lists 10 young and 11 elderly mice given IL-2/CD40
  • After IL-2/anti-CD40 treatment, CD8+ T cells in tumor-draining lymph nodes of young mice up-regulated perforin, giving higher levels than in elderly treated mice
  • Tumor-specific killing activity by T cells was significantly lower in tumor-draining lymph nodes and tumors of elderly mice than young mice, in both IL-2/CD40-treated and PBS control groups
• The authors' conclusion: The authors concluded that aging programs a suppressive immune environment that is maintained in mesothelioma-bearing mice and may have contributed to the reduced effect of IL-2/CD40 in elderly mice. They suggested that combining IL-2/CD40 with checkpoint blockade could improve therapy in elderly hosts with mesothelioma.
• Limitations the authors state:
  • The age-related immune differences during treatment were measured after only two of the five doses (one-third of the usual schedule), so the authors said further studies after a complete schedule are required

Topics

Medical terms in this study, explained in our Lexicon: Immunotherapy, Mesothelioma, CTLA-4.

Related studies

• Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy — L. Noordam, M.E.H. Kaijen, et al. (2018)
• 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)
• 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, J.K. Gardner, et al. (2019)
• Hyperplastic mesothelial cells in lymph nodes: report of six cases of a benign process that can stimulate metastatic involvement by mesothelioma or carcinoma — P. Argani, J. Rosai (1998)
• Mesothelial cell inclusions mimicking adenocarcinoma in cervical lymph nodes in association with chylous effusion — M. Goyal, S. Kodandapani, et al. (2010)
• Tumour-derived exosomes as antigen delivery carriers in dendritic cell-based immunotherapy for malignant mesothelioma — N.M. Mahaweni, M.E. Kaijen-Lambers, et al. (2013)

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