Immunosenescence: a key player in cancer development

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 NAD⁺ 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: Aging; Cancer immunotherapy; Immunosenescence; Tumor microenvironment; Tumor progression.

Fig. 1

The process of immunosenescence. The process of immunosenescence can alter the immune response, thus leading to the occurrence of various diseases, such as tumors and infections. Many factors can activate the immunosenescence process: the thymus gradually degenerates, resulting in an age-related decrease in T cell output and leading to the senescence of the immune system; inflammation related to advanced age will produce SASP, which also leads to immunosenescence; the intrinsic factors in immune system cells as well as potential extrinsic factors that are often overlooked, can also cause immunosenescence

Fig. 2

The main markers of immunosenescence. The main feature of immunosenescence is the degeneration of the thymus, which is accompanied by a decrease in IL-7 secretion. Senescence is accompanied by a decrease in telomere length and telomerase activity. Senescence T cells show reduced SA-β-galactosidase activity, cytotoxic activity, expression of functional molecules such as IFN-γ, scarce proliferation, and also arrested cell cycle, due to an increase of the related proteins, P16 and P21. During the remodeling of the immune system with age, changes in immune cell markers are mainly characterized by the loss of CD27 and CD28 expression and the increase in CD57 and KLRG-1 expression. During aging, glycolysis and ROS production are increased, while mitochondrial synthesis is decreased

Fig. 3

T cell senescence-related signaling pathways. Tumor-derived cAMP can be transferred to T cells, activating the PKA-CREB signaling pathway, which in turn activates DNA damage and induces T cell senescence. T cell competition for glucose triggers ATM-related DNA damage, activates the ERK1/2 and P38 pathways, and interacts with STAT1/3, which leads to T cell cycle arrest and aging. Activation of the P38 pathway induces the downregulation of TERT, leading to DNA damage. The downregulation of TCR signaling can activate the P38 pathway and inhibit the PI3K-AKT-mTOR signaling pathway, thereby inactivating autophagy and inducing mitochondrial dysfunction and ROS production in senescent T cells. DNA damage induced by the GATA4-C/EBPβ signaling pathway leads to increased secretion of SASP molecules. Similarly, the cGAS-STING signaling pathway also leads to increased secretion of SASP molecules

Fig. 4

Changes in various immune cell subsets during immunosenescence. Many immune cell subpopulations are altered during immunosenescence. Number of both naive T and B cells is decreased, but the number of memory T and B cells is increased. In the aging process, the diversity of TCR decreases with age. In addition, antigen recognition and presentation capabilities are reduced. In addition, the antigen presentation and phagocytosis ability of DC cells are reduced. NK cell function is reduced. The number and function of MDSCs and macrophages are increased

Fig. 5

The effect of an aging TME on tumor progression. Age-induced changes in the structure and function of the ECM promote the occurrence and development of tumors. The integrity of the ECM is greatly reduced with age, which can promote the development of cancer. In the aging TME, stromal cells are disordered and loosely arranged, which may also lead to tumor progression and metastasis. Moreover, age-induced secretion of SASP, such as the accumulation of several factors, including IL-6, IL-8, and IL-10, is a key factor in inducing tumorigenesis and progression. The aging TME also exhibits an infiltration of immunosuppressive cells, such as MDSCs and Tregs. The increase in immunosuppressive M2 macrophages and N2 neutrophils may further promote immunosuppression, while immunosenescence of effector T cells, NK cells, macrophages, and DCs significantly reduces their cytotoxic activity, leading to tumor escape and tumor progression