Cytokine-Induced Senescence in the Tumor Microenvironment and Its Effects on Anti-Tumor Immune Responses

Abstract

In contrast to surgical excision, chemotherapy or radiation therapy, immune checkpoint blockade therapies primarily influence cells in the tumor microenvironment, especially the tumor-associated lymphocytes and antigen-presenting cells. Besides complete remission of tumor lesions, in some patients, early tumor regression is followed by a consolidation phase where residing tumors remain dormant. Whereas the cytotoxic mechanisms of the regression phase (i.e., apoptosis, necrosis, necroptosis, and immune cell-mediated cell death) have been extensively described, the mechanisms underlying the dormant state are still a matter of debate. Here, we propose immune-mediated induction of senescence in cancers as one important player. Senescence can be achieved by tumor-associated antigen-specific T helper 1 cells, cytokines or antibodies targeting immune checkpoints. This concept differs from cytotoxic treatment, which often targets the genetic makeup of cancer cells. The immune system's ability to establish "defensive walls" around tumors also places the tumor microenvironment into the fight against cancer. Those "defensive walls" isolate the tumor cells instead of increasing the selective pressure. They also keep the tumor cells in a non-proliferating state, thereby correcting the derailed tissue homeostasis. In conclusion, strengthening the senescence surveillance of tumors by the immune cells of the microenvironment is a future goal to dampen this life-threatening disease.

Keywords: T cells; cell cycle regulation; cell death; chemoresistance; growth arrest; immunotherapy; inflammatory cytokines; senescence surveillance; tumor dormancy; tumor microenvironment.

Figure 1

Deranged tissue homeostasis in hyperplastic tumors. (A) Under physiological conditions, the size of a specialized tissue is kept constant (beige cells). Tissue homeostasis is a steady state where tissue generation by cell proliferation (blue arrow on the left) and clearance of damaged or old cells by apoptosis or cellular senescence (blue arrow on the right) are kept in balance. (B) High levels of growth factors or the activation of oncogenes lead to hyperproliferation (enlarged blue arrow on the left), and loss of tumor suppressors cause reduced apoptosis or cellular senescence (narrowed blue arrow on the right). This dysfunctional tissue homeostasis evokes excessive tissue formation and hyperplastic tumor growth (grey cells).

Figure 2

Overview of the components of the tumor microenvironment (TME). The cellular composition of the TME is quite heterogeneous and consists of various cell types. These include (i) tumor cells (upper right) as well as (ii) stromal cells (lower left) and (iii) immune cells (lower right). Soluble factors secreted by the cells of the TME (red stars) also play an important role, as do structural components, such as (iv) the extracellular matrix (ECM; upper left).

Figure 3

Cytotoxic and non-cytotoxic tumor immune control. The cartoon summarizes the control of a tumor by non-toxic mechanisms executed by CD4⁺ T cells that secrete pro-inflammatory cytokines (upper part of the cartoon) or toxic mechanisms executed by tumor-infiltrating cytotoxic CD8⁺ T cells (lower part of the cartoon). Abbreviations: SASP, senescence-associated secretory phenotype; TME, tumor microenvironment.

Figure 4

Senescence induction and its impact on neighboring cells. After encountering a senescence trigger (orange lightning), the cells start to change. They adopt a flattened morphology and enlarge in size. Besides being growth-arrested, the cells show increased activity of the senescence-associated β-galactosidase (SA-β-gal), metabolic changes, chromatin remodeling and an altered gene expression, including the formation of a senescence-associated secretory phenotype (SASP). This SASP then acts in an autocrine or paracrine manner, influencing the senescent cells themselves as well as neighboring cells in the tissue.