Modulation of dendritic cell and T cell cross-talk during aging: The potential role of checkpoint inhibitory molecules

Gardner, Joanne K.; Mamotte, Cyril; Jackaman, Connie; Nelson, Delia J.

doi:10.1016/j.arr.2017.07.002

Cited by 28 publications

(18 citation statements)

References 165 publications

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“…This may impair the priming of T cells and furthermore inhibit the polarization of Th cells. Currently, the mechanisms of cross talk between DCs and T cells need to be clarified, although a role for checkpoint inhibitors has been proposed [ 174 ]. In cancer studies, there is clear evidence that MDSCs inhibit the functions of DCs [ 78 ].…”

Section: Introductionmentioning

confidence: 99%

Immunosenescence: the potential role of myeloid-derived suppressor cells (MDSC) in age-related immune deficiency

Salminen

Kaarniranta

Kauppinen

2019

Cell. Mol. Life Sci.

112

126

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The aging process is associated with chronic low-grade inflammation in both humans and rodents, commonly called inflammaging. At the same time, there is a gradual decline in the functional capacity of adaptive and innate immune systems, i.e., immunosenescence, a process not only linked to the aging process, but also encountered in several pathological conditions involving chronic inflammation. The hallmarks of immunosenescence include a decline in the numbers of naïve CD4 + and CD8 + T cells, an imbalance in the T cell subsets, and a decrease in T cell receptor (TCR) repertoire and signaling. Correspondingly, there is a decline in B cell lymphopoiesis and a reduction in antibody production. The age-related changes are not as profound in innate immunity as they are in adaptive immunity. However, there are distinct functional deficiencies in dendritic cells, natural killer cells, and monocytes/macrophages with aging. Interestingly, the immunosuppression induced by myeloid-derived suppressor cells (MDSC) in diverse inflammatory conditions also targets mainly the T and B cell compartments, i.e., inducing very similar alterations to those present in immunosenescence. Here, we will compare the immune profiles induced by immunosenescence and the MDSC-driven immunosuppression. Given that the appearance of MDSCs significantly increases with aging and MDSCs are the enhancers of other immunosuppressive cells, e.g., regulatory T cells (Tregs) and B cells (Bregs), it seems likely that MDSCs might remodel the immune system, thus preventing excessive inflammation with aging. We propose that MDSCs are potent inducers of immunosenescence.

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Section: Introductionmentioning

confidence: 99%

Immunosenescence: the potential role of myeloid-derived suppressor cells (MDSC) in age-related immune deficiency

Salminen

Kaarniranta

Kauppinen

2019

Cell. Mol. Life Sci.

112

126

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“…This may be because tumors grow at a faster rate, meaning elderly mice had larger tumors leading to higher levels of factors associated with cancer cachexia, such as IL-6. 28 Therefore, distorted cytokine secretion on account of inflammaging that is further amplified by tumors in the elderly alongside increased expression of exhaustion/checkpoint molecules on T cells such as PD-1 and CTLA-4 29,30 and dendritic cells such as PDL-1/2 [31][32][33] may account for the loss of functional responses to dominant epitopes. Indeed, we have data showing that elderly CD8 + T cells from tumor draining LNs express higher levels of all enzymes and receptors involved in the adenosine pathway (CD39, CD73, A2AR and A2BR), as well as higher PD-1, ICOS, CTLA-4, LAG3, IL-10 and TGFβ relative to their younger counterparts; this difference was amplified in elderly mice treated with both chemotherapies (manuscript under review).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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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. ARTICLE HISTORY

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“…Collectively, age-related changes and alterations in signaling pathways are complex and interconnected. These changes are likely to influence DC, Teff, and Treg pathways, increasing the likelihood of T cell suppression in the elderly ( 79 ). Indeed more research is needed to understand the link between age-related cellular and molecular changes and their potential influence on DC and T cell pathways leading to the development of autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the loss of costimulatory molecules, there is an increase in the expression of inhibitory receptors, which adds to T cell dysfunction during aging ( 79 ). The expression of the inhibitory checkpoint molecule, CTLA-4 increases with age ( 80 ), whereas the expression of PD-1 is considered to be dependent on viral status rather than age and may also serve as a useful marker on viral-specific CD8+ T cells to indicate the degree of T cell exhaustion ( 41 ).…”

Section: Impact Of Aging and Immunosenescence On Checkpoint Molecule mentioning

confidence: 99%

Checks and Balances in Autoimmune Vasculitis

et al. 2018

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Age-associated changes in the immune system including alterations in surface protein expression are thought to contribute to an increased susceptibility for autoimmune diseases. The balance between the expression of coinhibitory and costimulatory surface protein molecules, also known as immune checkpoint molecules, is crucial in fine-tuning the immune response and preventing autoimmunity. The activation of specific inhibitory signaling pathways allows cancer cells to evade recognition and destruction by the host immune system. The use of immune checkpoint inhibitors (ICIs) to treat cancer has proven to be effective producing durable antitumor responses in multiple cancer types. However, one of the disadvantages derived from the use of these agents is the appearance of inflammatory manifestations termed immune-related adverse events (irAEs). These irAEs are often relatively mild, but more severe irAEs have been reported as well including several forms of vasculitis. In this article, we argue that age-related changes in expression and function of immune checkpoint molecules lead to an unstable immune system, which is prone to tolerance failure and autoimmune vasculitis development. The topic is introduced by a case report from our hospital describing a melanoma patient treated with ICIs and who subsequently developed biopsy-proven giant cell arteritis. Following this case report, we present an in-depth review on the role of immune checkpoint pathways in the development and progression of autoimmune vasculitis and its relation with an aging immune system.

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Modulation of dendritic cell and T cell cross-talk during aging: The potential role of checkpoint inhibitory molecules

Cited by 28 publications

References 165 publications

Immunosenescence: the potential role of myeloid-derived suppressor cells (MDSC) in age-related immune deficiency

Immunosenescence: the potential role of myeloid-derived suppressor cells (MDSC) in age-related immune deficiency

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

Checks and Balances in Autoimmune Vasculitis

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Modulation of dendritic cell and T cell cross-talk during aging: The potential role of checkpoint inhibitory molecules

Cited by 28 publications

References 165 publications

Immunosenescence: the potential role of myeloid-derived suppressor cells (MDSC) in age-related immune deficiency

Immunosenescence: the potential role of myeloid-derived suppressor cells (MDSC) in age-related immune deficiency

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

Checks and Balances in Autoimmune Vasculitis

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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