T cell senescence: a new perspective on immunotherapy in lung cancer

Abstract

T cell senescence is an indication of T cell dysfunction. The ability of senescent T cells to respond to cognate antigens is reduced and they are in the late stage of differentiation and proliferation; therefore, they cannot recognize and eliminate tumor cells in a timely and effective manner, leading to the formation of the suppressive tumor microenvironment. Establishing methods to reverse T cell senescence is particularly important for immunotherapy. Aging exacerbates profound changes in the immune system, leading to increased susceptibility to chronic, infectious, and autoimmune diseases. Patients with malignant lung tumors have impaired immune function with a high risk of recurrence, metastasis, and mortality. Immunotherapy based on PD-1, PD-L1, CTLA-4, and other immune checkpoints is promising for treating lung malignancies. However, T cell senescence can lead to low efficacy or unsuccessful treatment results in some immunotherapies. Efficiently blocking and reversing T cell senescence is a key goal of the enhancement of tumor immunotherapy. This study discusses the characteristics, mechanism, and expression of T cell senescence in malignant lung tumors and the treatment strategies.

Keywords: T cell; T cell senescence; immune senescence; immunotherapy; malignant lung tumor.

Figure 1

Differences between T-cell senescence and T-cell exhaustion.

Figure 2

Role of senescent T cells in tumorigenesis and development: (i) Senescent T cells have impaired anti-tumor activity. Moreover, down-regulation of the costimulatory molecules CD27 and CD28, as well as the effector molecules perforin and granzyme, reduces proliferation, promotes cell cycle arrest and inhibits the expression of proliferative molecules. (ii) senescent T cells directly affect immune cells and induce adaptive Tregs, but inhibit DC and effector T cells (iii) senescent T cells exhibit an aging-associated secretory phenotype, which produces abundant pro-inflammatory factors, such as interleukin (IL)-2, IL-6, IL-8, and interferon-γ, which interfere with normal cell differentiation, although they are leukin cells that are leukocyte leukin, which promotes the occurrence of malignant tumors; (iv) T cell senescence directly inhibits T cell proliferation and function; (v) T cell senescence directly promotes tumor growth, invasion, metastasis, and epithelial-mesenchymal transformation.

Figure 3

Mechanisms of T cell senescence and ways to reverse T cell senescence.