Interleukins and related cytokines are means of communication between innate and adaptive immune cells as well as non-immune cells and tissues. Therefore, interleukins play a key role in the occurrence, development and control of cancer, and some interleukins are particularly relevant to the occurrence and development of cancer. A variety of cellular sources, receptors and signaling pathways determine the pleiotropic effects of interleukins in cancer. Interleukins foster an environment conducive to cancer growth and are also necessary to generate tumor-directed immune responses.
Tumorigenesis
Chronic inflammation has long been thought to be one of the drivers of many cancers. Some interleukins directly induce signaling in non-immune cells and maintain tissue homeostasis. However, following cancer development, interleukin signaling in cancer cells becomes a pathological mechanism for tumor growth, metastatic spread, and progression.
IL-1 has long been implicated in inflammation-induced carcinogenesis. pro-IL-1β responds rapidly to Danger-Associated Molecular Patterns (DAMPs) and Pathogen-Associated Molecular Patterns (PAMPs) via pathogen-recognition receptors such as Toll-like receptors, C-type lectin receptors, or RIG-I-like receptors .
In the context of chronic inflammation, IL-1α and IL-1β may directly promote the production of oncogenic mediators such as NO and ROS, as well as the production and release of IL-6, IL-11 and IL-22. IL-6, IL-11, together with IL-22, rapidly induce phosphorylation of STAT3, and activation of STAT3 signaling can be observed in multiple types of cancer, inducing proliferation, survival, epithelial-mesenchymal transition (EMT), and transformed cells migration.
IL-1β, together with TGF-β, induces T helper 17 (TH17) differentiation, which secretes IL-17A and IL-17F (IL-17A/F) after stimulation with IL-23. IL-17, which normally mediates wound-healing signals, may also exacerbate new tumor growth.
Recent studies have shown that IL-33 can create a self-amplifying tumorigenic ecosystem and promote the development of new tumors. Once cells transform, they acquire tumorigenic capacity, as shown in the squamous cell carcinoma model. Tumor-initiating cells secrete IL-33, which in turn leads to infiltration of tumor-associated macrophages and promotes the production of tumorigenic signals by TGF-β.
Tumor growth and progression
Malignant tumors have important characteristics, namely persistent proliferation, inflammation, angiogenesis, active invasion and migration, which are also hallmarks of wound healing, and thus, tumors may maliciously exploit cytokine signals aimed at tissue repair.
IL-1 not only promotes inflammation-induced carcinogenesis, but also contributes to tumor invasiveness and angiogenesis.
Some cancer types have been shown to overexpress certain cytokines, such as IL-6 or IL-11, which may activate the PI3K–AKT–mTOR pathway in an autocrine manner, thereby upregulating glycolysis and inducing metabolic reprogramming; Activation of NF-κB, RAS-RAF-MAPK and STAT3 signaling pathways, which promote EMT, proliferation, migration, reduction of apoptosis, and the production of cytokines such as IL-8 and VEGF, thereby inducing angiogenesis.
Other cytokines, such as IL-1β, IL-13, IL-17, IL-22, IL-23, and IL-35, can also induce EMT, leading to tumor progression.
Tumor-secreted IL-8 induces the recruitment of polymorphonuclear leukocytes (PMNs), which, together with monocytes, differentiate into myeloid-derived suppressor cells (MDSCs) that suppress T helper 1 (TH1) responses.
TGF-β, together with IL-33, promotes the differentiation of Treg cells, which inhibit the antitumor response. In addition, TGF-β and IL-6 can promote the differentiation of TH17 cells to produce IL-17, which further promotes the recruitment and differentiation of MDSCs.
Tumor immune surveillance
Innate immunity
Natural Killer (NK) cells have multiple receptors that allow the recognition and elimination of transformed cells. Danger-associated molecular patterns, such as high mobility group protein B1 (HMGB1) released from malignant cells, are processed by antigen-presenting cells such as DCs and MΦs. These cells in turn produce IL-12 and IL-15, which promote the cytotoxic activity of NK cells and CTLs and induce IFN-γ release.
IL-18 acts through its highly expressed receptor in NK cells and triggers IFN-γ production, cytotoxicity and FAS ligand (FASL) expression.
IL-28A, IL-28B and IL-29 are cytokines that are distantly related to the IL-10 family and are also interferons, so they are also called “type III interferons” or “λ-interferons”. They usually mediate innate immune antiviral activity, but also directly induce apoptosis in malignant cells.
Adaptive immunity
After the death of immunogenic cancer cells, antigens released by tumor cells are taken up by APCs and enter the draining lymph nodes to initiate the formation of antigen-specific adaptive immune responses. Here, the cytokine milieu plays a decisive role in T cell fate. The proliferation, survival, differentiation and termination of T cell responses are mainly controlled by IL-2, IL-7 and IL-15, whereas IL-3 is required for the survival and proliferation of lymphocyte progenitors.
CTL and effector TH1 cells are major mediators of antitumor adaptive immunity. DC-derived IL-12 provides the necessary signal to drive T-bet expression, thereby promoting the differentiation of effector TH1 cells and CTLs. Similar to signaling in NK cells, IL-2, IL-15 and IL-18 cooperate with IL-12 to trigger IFN-γ production and direct cytotoxicity of CTL and TH1 cells.
In addition, DCs, together with M1 macrophages, produce IL-12, which is necessary to maintain TH1 cell polarization and IFN-γ expansion. IL-10 secreted by M1 macrophages, IL-27 secreted by macrophages and DC cells, and IL-21 produced by H17 cells and follicular helper T cells may also enhance cytotoxicity.
Tumor immune evasion
Despite the powerful roles of tumor immune surveillance and immune editing, malignant cells may still evolve to evade antitumor responses and utilize exogenous immunosuppressive mechanisms to promote tumor progression.
Treg
High-affinity IL-2 signaling and TGFβ induce Foxp3, and FOXP3 can promote Treg cell differentiation and IL-10 production, thereby establishing an immunosuppressive TME. IL-33 can also directly promote TGF-β-induced Treg cell differentiation, inhibit IFN-γ and promote the stability of Treg cells in tumors.
The regulation of Treg cells in TME is mainly mediated by the secretion of IL-10, IL-35 and TGF-β. IL-10 has anti-inflammatory effects, while IL-35 induces the expression of inhibitory surface receptors (including PD1, LAG3, TIM3, TIGIT, and CD244) and limits T cell memory formation.
TH17-type responses and myeloid inhibitors
IL-1β stimulates TH17 cells and γδ T cells to produce IL-17, which recruits a large number of immunosuppressive granulocytes. Furthermore, in lung cancer, IL-23 converts group 1 innate lymphocytes into IL-17-producing ILC3s, thereby promoting IL-17-mediated tumor cell proliferation.
In addition, tumor-derived IL-8 (also known as CXCL8) provides chemotactic signals to myeloid cells in breast cancer patients and develops resistance to immunotherapy. Likewise, IL-18 produced after inflammasome activation drives the generation of MDSCs in multiple myeloma, resulting in an immunosuppressive mechanism.
TH2 type reaction
Tumor and stromal cells may secrete cytokines that promote polarization of TH2 cells and M2 macrophages, thereby inhibiting antitumor TH1 cell polarization and responses. Likewise, IL-33-induced group 2 innate lymphocytes (ILC2) were shown to antagonize NK cell function in a mouse melanoma model. In turn, IL-33 secreted by breast cancer-associated fibroblasts is a potent enhancer of ILC2- and TH2-type responses, possibly inducing TCR-independent secretion of IL-13 and recruiting immunosuppressive granulocytes.
Metabolic reprogramming of immune cells
Cancer cells can induce metabolic reprogramming and changes in the metabolic system of TME immune cells, thereby inducing a shift from an inflammatory response to an immunosuppressive response. The NF-κB-inducible kinase (NIK)-dependent glycosylation switch in effector T cells was shown to be critical for antitumor immunity in a mouse melanoma model. Accumulation of lactate-derived glycolysis in the TME increases oxidative phosphorylation and induces anti-inflammatory reprogramming together with IL-4.
Furthermore, accumulation of lactate in the TME and depletion of amino acids and glucose in combination with TGF-β signaling induces Treg cell polarization, enhanced immunosuppression and T cell exhaustion, thereby rendering tumors resistant to immunotherapy. In pancreatic ductal adenocarcinoma, stromal cells release IL-6, which increases glycolysis and lactate extravasation in tumor cells, leading to M2 polarization of macrophages and a decrease in the efficacy of anti-PD1 therapy.
Therefore, the accumulation of tumor-derived substances and chronic inflammatory responses make anti-tumor immunity unable to inhibit tumor growth and progression, leading to uncontrolled tumor growth and distant metastasis, limiting the effect of targeted therapy.
