State-of-the-art Insights into the Immuno-Oncological Effect of Aging and Circadian Rhythm

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Background

Aging and circadian rhythm are growing in popularity in the research of malignant tumors. Targeting these processes has shown various preventive and therapeutic efficiencies in human cancer.

We are in an aging society worldwide. Aging is characterized by an increased vulnerability to infection and the development of inflammatory diseases, including cancer and neurodegeneration, and is related to different physiological changes, such as the circadian timing system. Current studies also demonstrate that circadian rhythm is dysregulated in age-related diseases, including a variety of malignant tumors. Circadian rhythms temporally coordinate cellular, tissue, and behavioral functions to maximize physiology and health. Age-related dampening of these endogenous rhythms impairs temporal coordination. It was found that aging was associated with the loss of diurnally rhythmic innate immune responses and this decline in homeostatic immune responses was associated with a striking disappearance of circadian gene transcription in aged compared to young tissue macrophages. Experts established cell-type proportion-based clock models to predict age using human blood peripheral blood mononuclear cells and found that supercentenarians were much younger than their actual age. In addition, individuals in a disease state had a higher average biological age, which increased with disease severity. Moreover, compared with the general population, the overall number of T cells in the naturally long-lived elderly does not change, but the proportion of cytotoxic T cells is higher.

Senescent cells can interact with their environment often, changing the microenvironment and possibly burdening the tissue. Immune cells, such as T and B cells, display senescent-like phenotypes and accumulate during aging, namely immune senescence. This process could mitigate the function of the immune system, but it could be used to eliminate tumor cells. For example, the immunogenicity of senescent cells was enhanced. On the other hand, senescent cells lingering in the tumor microenvironment (TME) can contribute to tumor progression, metastasis, and therapy resistance. For example, senescent tumor cells could evade NK cell immunity by downregulating surface NKG2D ligands or upregulating HLA-E molecules to bind to the NKG2A receptor. Targeting the relevant molecules with antibodies can be a potential strategy to disrupt this immune evasion mechanism. Meanwhile, there are ongoing clinical developments for drugs aimed at blocking the NKG2A checkpoint or preventing the shedding of NKG2D ligands MICA/B.

In addition, SASP (senescence-associated secretory phenotype) serves as an effector arm of cellular senescence, which can also enhance the infiltration and immune suppressive properties of MDSCs (myeloid-derived suppressor cells) and other myeloid cells known to inhibit NK and T cell functionality. Therefore, another approach to enhance anti-tumor immunity is by targeting these specific populations and the signaling mechanisms that attract them.

In this Research Topic, we systematically explored the biodiversity of aging and circadian rhythm in the tumor immune microenvironment and their targeted effects on human cancer. We welcome authors to contribute Original Research articles, Review articles, and Perspectives that concentrate on the crosstalk among immune, aging, and circadian rhythm in cancer. Potential subtopics include, but are not limited to:
(1) Exploring the patho-physiological traits of aging and circadian rhythm in tumor immune microenvironment.
(2) Effect of drugs targeting aging or circadian rhythm on tumor immune microenvironment and their mechanism.
(3) Whether aging and circadian rhythm are associated with immuno-oncological response?
(4) How to use aging and circadian rhythm to enhance antitumor immune responses?

Please NOTE: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of the scope for this section and will not be accepted as part of this Research Topic.

Keywords: Aging, Circadian Rhythm, cancer, tumor immune microenvironment

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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