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.

Joanne K Gardner,Connie Jackaman,Delia J Nelson,Cyril D S Mamotte

doi:10.3389/fmed.2018.00337

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.

Highlights

There is an increased incidence of cancer with aging, and one contributing factor could be age-induced modulation of immune cells that mediate anti-tumor immune responses, such as dendritic cells (DCs) and T cells
Our study shows that aging programs development of a suppressive immune environment, which is reflected by DCs and T cells, and this may compromise generation of antitumor immune responses, influence mesothelioma progression and responses to IL-2/CD40 immunotherapy
As tumor-draining LNs (TDLNs) are the main site of DC/T cell interactions leading to generation of anti-tumor effector T cell responses, increased suppressive mechanisms in elderly TDLNs likely led to compromised generation of anti-mesothelioma effector T cell responses, thereby contributing to the faster tumor growth rate observed in the elderly

Summary

Introduction

There is an increased incidence of cancer with aging, and one contributing factor could be age-induced modulation of immune cells that mediate anti-tumor immune responses, such as dendritic cells (DCs) and T cells. Age-related defects in murine T cell anti-tumor function have been reported, these include; reduced numbers of tumor-antigen-specific T cells, decreased proliferative capacity, impaired cytotoxic activity, and reduced production of effector cytokines, such as interferon (IFN)-γ and IL-2, in elderly tumor-bearing mice [10,11,12,13,14,15,16,17,18]. The effects of healthy aging on DCs and T cells, and the potential impact on generation of anti-tumor immune responses in mesothelioma, an asbestos-induced cancer which occurs predominantly in elderly populations aged 60 years and above [19, 20], have not yet been reported

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