Table 1 An overview of the tumour-suppressing and tumour-promoting roles of the IL-36 family members and IL-38 in cancer.
From: The complex roles of IL-36 and IL-38 in cancer: friends or foes?
Anti-tumorigenic function | Tumour type | |
|---|---|---|
IL-36α | Suppression of tumour cell proliferation, migration and invasion Enhanced function of tumour infiltrating CD8+ T cells Regulation of NF-κB and MAPK pathways to promote M1 macrophage activity and tumour infiltration Disruption of angiogenesis via HIF-1α downregulation Synergisation with PD-L1 for increased anti-tumour response Expression associated with improved patient prognosis | Human epithelial ovarian [62], human HCC [66], mouse melanoma [63] Human HCC [65], mouse colorectal [69] Mouse melanoma [63] Human NSCLC [72] Melanoma [63] Human epithelial ovarian [62], human thymoma, kidney renal clear cell carcinoma and melanoma [63], human HCC [65, 66], human colorectal [67], human NSCLC [72] |
IL-36β | Increased tumour infiltration of CD8+ T cells Increased IFN-γ and IL-2 expression by CD8+ T cells via mTORC1 activation Downregulated activity of CD8+ T cell functional inhibitor let-7c-5p Expression associated with improved patient prognosis | Mouse melanoma [64], mouse pancreatic [71] Mouse melanoma [64] Mouse and human pancreatic [71] Human kidney renal clear cell carcinoma and melanoma [63], mouse melanoma [64], mouse pancreatic [71] |
IL-36γ | Suppression of tumour cell proliferation and migration Increased tumour infiltration of NK and γδ T cells Enhanced function of tumour infiltrating CD8+ T cells Promotion of a type 1 immune response via increased IFN-γ, IL-12 and TNF-α expression Increased sensitivity to CTLA-4 immunotherapy Increased TIL activity Increased expression of PMN-MDSCs Promotion of intra-tumoral TLS formation IL-36γ/IL-23/OX40L mRNA triplet promoted anti-cancer activity and efficiency of checkpoint blockade Expression associated with improved patient prognosis | Mouse melanoma and breast [70], mouse colorectal [80] Mouse melanoma [70], mouse colorectal [80] Mouse breast [70] Mouse melanoma [70] Mouse melanoma [79] Mouse melanoma [73], mouse colorectal [80] Mouse melanoma [73] Mouse colorectal [76] Mouse colorectal [80] |
IL-36RA | Regulation of JNK signalling to inhibit cell adhesion and ECM gene expression Inhibition of Wnt signalling Promotion of CD8+ tumour infiltration Expression associated with improved patient prognosis | Mouse colorectal [85] Mouse colorectal [85] Mouse colorectal [84] Mouse NSCLC [87] |
IL-38 | Regulates ERK pathway to reduce tumour cell proliferation and migration Associated with increased tumour infiltration of CD4+ and CD8+ T cells Associated with reduced PD-1 expression Inhibited inflammatory chemokine production via NF-κB / MAPK disruption Expression associated with improved patient prognosis | Human colorectal [99] Human colorectal [98] Human colorectal [98] Human colorectal [58] Human colorectal [98] |
Pro-tumorigenic function | Tumour type | |
IL-36α | Promoted inflammatory chemokine expression Promoted tumour cell proliferation Regulated p42/44 MAPK pathway Expression associated with poorer patient prognosis | Human and mouse NSCLC [82] Human and mouse colorectal [84] Human NSCLC [82] Human NSCLC [82] |
IL-36β | Promoted inflammatory chemokine expression Promoted tumour cell proliferation Regulated p42/44 MAPK pathway | Human and mouse NSCLC [82] Human and mouse colorectal [84] Human NSCLC [82] |
IL-36γ | Promoted tumour cell proliferation Regulated p42/44 MAPK and P13K/AKT pathways Synergised with the IL-17A/IL-22 signalling axis Promoted inflammatory chemokines expression (CCL2, CCL20, CXCL1, LCN2, IL-8) Regulated JNK signalling to promote cell adhesion and ECM gene expression Regulated Wnt signalling Neutralised reactive oxygenase species Promoted epithelial cell transformation Promoted tumoral expression of PD-L1 Expression associated with poorer patient prognosis | Human and mouse colorectal [84, 85], human NSCLC [82], human gastric [83], human oral squamous cell carcinoma [86] Human colorectal [84], human NSCLC [82] Human colorectal [81], human NSCLC [82] Human and mouse NSCLC [82], human colorectal [85] Human and mouse colorectal [85] Mouse colorectal [85] Mouse NSCLC [87] Human breast [88] Human NSCLC [82] Mouse NSCLC [87], human colorectal [67], human NSCLC [82], human gastric [83] |
IL-36RA | Associated with increased intra-tumoral PD-1, PD-L1 and CTLA4 expression | Human colorectal [77] |
IL-38 | Regulated JNK/AP-1 signalling to promote cell proliferation, migration and inflammatory chemokine and cytokine production Reduced tumour infiltration of CD8+ T cells Reduced tumour infiltration of NK and B-cells Expression associated with poorer patient outcome | Human and mouse squamous cell carcinoma [96] Human prostate [92], mouse lung [94], mouse breast [95] Squamous cell carcinoma [93] Human breast cancer [95], human NSCLC [90], human prostate [92] |
