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.

Comprehensive Analysis of Senescence Characteristics Defines a Novel Prognostic Signature to Guide Personalized Treatment for Clear Cell Renal Cell Carcinoma

“…Identified SASP factors include soluble signaling molecules (e.g., interleukins, chemokines, inflammatory factors, and growth factors), proteases, and ECM components ( 17 ). Actually, it has long been noted that the stromal fibroblasts manipulate the pro-tumoral/anti-tumoral role of senescence through the SASP phenotype-associated secretion profiles ( 17 , 36 , 37 ). For example, MMP-2 and MMP-9, which are mainly secreted by CAFs, have been shown to be associated with RCC progression ( 38 ).…”

A Four-Cell-Senescence-Regulator-Gene Prognostic Index Verified by Genome-Wide CRISPR Can Depict the Tumor Microenvironment and Guide Clinical Treatment of Bladder Cancer

“…The immune cells consist of tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), tumor-infiltrating lymphocytes (TILs), and myeloid-derived suppressor cells (MDSCs). The stromal cells include endothelial cells, cancer-associated fibroblasts (CAFs), and other cells ( 53 ). As mentioned above, SASP was characterized by increased secretion of multiple pro-inflammatory and pro-regenerative factors, which could attract and activate immune cells in the TME to clear the senescent cells and maintain the tissue homeostasis or lead to senescence escape and tumor progression, which depends on the kinds of immune cells and factors in the TME.…”

“…CCR was important for TAMs to accumulate in the TME, and HLA, also called MHC, was essential to the activation of adaptive antitumor immunity and recognition of tumor cells by NK cells and CD8+ T cells ( 53 ). Moreover, IFN-γ could induce Th0 cells and M0 macrophages to differentiate into Th1 and M1 phenotype and exert anti-tumorigenic functions, and it could also induce senescence ( 53 ). Besides, we discovered that the NK T cells, which were crucial to the antitumor immunity ( 54 ), were negatively connected with the risk score.…”

“…We also noticed that the expressions of some immune checkpoints were negatively connected with the risk score with statistical significance, but for those commonly used for immunotherapy target such as PD-1, CTLA-4, and LAG-3, there existed no statistical difference between the high-and low-risk score subgroups. Moreover, we also found that the functions of immune cells in the high-risk score subgroup were partially aberrant compared to the low-risk score subgroup, such as expression of chemokine receptor (CCR) and HLA, secreting inflammation-promoting factors and response to IFN-g. CCR was important for TAMs to accumulate in the TME, and HLA, also called MHC, was essential to the activation of adaptive antitumor immunity and recognition of tumor cells by NK cells and CD8+ T cells (53). Moreover, IFN-g could induce Th0 cells and M0 macrophages to differentiate into Th1 and M1 phenotype and exert anti-tumorigenic functions, and it could also induce senescence (53).…”

Senescent Tumor Cells in the Peritoneal Carcinomatosis Drive Immunosenescence in the Tumor Microenvironment

“…Unlike in PC patients, in the PC model, animals were not treated with chemotherapeutics, indicating that neither therapy-induced senescence (TIS) nor OIS are the sole inducer. Given that in PC, the level of IFN-γ is upregulated and the peritoneal cavity harbors peritoneal macrophages that secrete high levels of TNF, we suspect cytokine-induced senescence as the inducer ( 8 , 9 , 60 ).…”