Immunosenescence: a key player in cancer development
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REVIEW
Immunosenescence: a key player in cancer development Jingyao Lian1,2†, Ying Yue1,2,3†, Weina Yu1,2† and Yi Zhang1,2*
Abstract Immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling of lymphoid organs, leading to changes in the immune function of the elderly, which is closely related to the development of infections, autoimmune diseases, and malignant tumors. T cell–output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species. Senescent T cells exhibit abnormal phenotypes, including downregulation of CD27, CD28, and upregulation of CD57, killer cell lectin-like receptor subfamily G, Tim-3, Tight, and cytotoxic T-lymphocyte-associated protein 4, which are tightly related to malignant tumors. The role of immunosenescence in tumors is sophisticated: the many factors involved include cAMP, glucose competition, and oncogenic stress in the tumor microenvironment, which can induce the senescence of T cells, macrophages, natural killer cells, and dendritic cells. Accordingly, these senescent immune cells could also affect tumor progression. In addition, the effect of immunosenescence on the response to immune checkpoint blocking antibody therapy so far is ambiguous due to the low participation of elderly cancer patients in clinical trials. Furthermore, many other senescence-related interventions could be possible with genetic and pharmacological methods, including mTOR inhibition, interleukin-7 recombination, and N AD+ activation. Overall, this review aims to highlight the characteristics of immunosenescence and its impact on malignant tumors and immunotherapy, especially the future directions of tumor treatment through senescence-focused strategies. Keywords: Immunosenescence, Tumor progression, Aging, Tumor microenvironment, Cancer immunotherapy Background The morbidity and mortality rates of various tumors increase with age, and thus, malignant tumors are generally defined as aging diseases [1, 2]. It should be noted that aging is generally defined as a decline of function in living organisms that occurs in a time-dependent manner and is associated with cancer progression [3]. Despite many studies considering aging as a tumor-suppressor mechanism, most senescent cells behave abnormally, which may eventually lead to serious outcomes, such as *Correspondence: [email protected] † Jingyao Lian, Ying Yue, and Weina Yu contributed equally to this work 1 Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450052, Henan, China Full list of author information is available at the end of the article
the development of tumors. Moreover, the accumulation of DNA damage, a critical driver of senescence, and the concomitant events associated with cellular senescence have been shown to participate in tumorigenesis. These studies also documented that cellular senescence is a cellular
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