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iNature Interleukin 37b (hereafter referred to as IL-37) was identified as a fundamental inhibitor of innate and acquired immunity
.
The molecular mechanism and function of IL-37 in colorectal cancer (CRC) have been elusive
.
On January 20, 2022, Li Jiong and Teng Xiu of Sichuan University jointly published an online article entitled "Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction" in Signal Transduction and Targeted Therapy (IF=18).
, which found that IL-37 transgenic (IL-37tg) mice were highly susceptible to colitis-associated colorectal cancer (CAC) and had a significantly increased colonic tumor burden
.
However, IL-37 is dispensable for intestinal mutagenesis, CRC cell proliferation, apoptosis and migration
.
Notably, IL-37 suppressed protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models
.
IL-37-induced dysfunction antagonizes IL-18-induced CD8+ T cell proliferation and effector function, which is dependent on SIGIRR (single immunoglobulin interleukin 1 receptor-related protein)
.
Finally, this study observed that IL-37 levels were significantly elevated in CRC patients, positively correlated with serum CRC biomarker CEA levels, but negatively correlated with CD8+ T cell infiltration in CRC patients
.
Taken together, our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivating cytotoxic T cells and establish a newly defined suppressor IL-37/SIGIRR in the cancer immune cycle as a treatment for CRC.
target
.
Colorectal cancer is the leading cause of morbidity and mortality worldwide
.
CD8+ cytotoxic T lymphocytes (CTL) are the first immune cells to attack cancer
.
Several studies have determined the density of CD8+ CTLs at the tumor and invasive margins to assess the risk of recurrence in CRC
.
CD8+ CTL infiltration may serve as an independent predictor of favorable survival outcomes in CRC patients
.
CD8+ CTL infiltration is highly responsive to immune checkpoint blockers
.
These findings suggest that CD8+ CTLs are key defenders of CRC
.
CD8+ CTLs kill tumor cells mainly through IFN-γ-mediated or perforin-mediated mechanisms
.
IFN-γ, a CD8+ CTL-derived cytotoxic cytokine, can initiate tumor cell apoptosis by activating the JAK-STAT1-caspase3 cascade
.
The mechanism of perforin-mediated tumor killing is achieved through degranulation of CD8+ CTLs, such as the release of degranulated cargoes, including the cytotoxic proteins perforin and granzymes
.
Perforin promotes the formation of transmembrane pores, leading to the entry of granzymes into tumor cells and triggering apoptosis
.
Cytokines, as secreted proteins, can provide key cues to immune cells, so they are attractive candidate targets for cancer immunotherapy
.
IL-18, a member of the IL-1 family, drives MyD88–IRAK4–JNK signaling through a heterodimeric receptor composed of IL-18Rα and IL-18Rβ subunits
.
Previous studies reported that IL-18 synergized with IL-12 to stimulate the production of the cytotoxic cytokine IFN-γ in CD8+ T cells
.
Recombinant IL-18 has previously been observed to inhibit tumor progression in preclinical models of CRC
.
In addition, recombinant IL-18 has good safety and good tolerability in clinical trials as an anticancer drug
.
These findings redefine the critical role of IL-18 as an antitumor cytokine that fundamentally alters the immune tumor microenvironment
.
Interleukin 37 (IL-37), a new member of the IL-1 family, acts as a recently discovered inhibitor of IL-18, interfering with IL-18-dependent inflammatory factors (TNF-α, IL-18) in renal tubular epithelial cells -1β and IL-6)
.
Previous studies have demonstrated that a tripartite complex consisting of IL-37, SIGIRR and IL-18Ra is essential for the function of IL-37
.
SIGIRR is an orphan receptor and overexpression of SIGIRR inhibits IL-18 signaling in Jurkat and HepG2 cells
.
These findings suggest that SIGIRR may play a critical role in the inhibition of IL-18 signaling by IL-37
.
IL-37 monitors innate immunity and emerges as a key regulator of acquired immunity
.
Schematic diagram of the article (image from Signal Transduction and Targeted Therapy) IL-37 attenuates Th1 responses but promotes the production of Th2 cytokines (IL-13 and IL-4) in ConA, leading to liver injury
.
IL-37 stimulation increased the proportion of Tregs in subjects with infectious diseases and allergies
.
These findings suggest that IL-37 is an important regulator of T cell immune responses
.
Considering the anti-inflammatory properties of IL-37, IL-37 has been found to affect the development of some cancers, such as non-small cell lung cancer, hepatocellular carcinoma, cervical cancer, and colon cancer
.
However, the immunological roles and functional mechanisms of IL-37 remain elusive in the tumor microenvironment
.
Specifically, the role of IL-37 on CD8+ CTL tumor immune surveillance is unclear
.
Discovery and understanding of key molecules and biological processes will provide valuable guidance for developing effective cancer therapies
.
Many IL-1 family members exhibit crucial regulatory roles in antitumor immune responses, thereby affecting tumor immune escape
.
The functional mechanism of the novel IL-1 family member IL-37 in the tumor microenvironment is unclear
.
Here, the study demonstrates that the anti-inflammatory cytokine IL-37 can act as a key inducer of dysfunctional cytotoxic CD8+ T cells that promote colitis-associated carcinogenesis
.
Furthermore, this study shows that IL-37 antagonizes IL-18-induced cytotoxic activity of CD8+ T cells through its inhibitory receptor SIGIRR
.
These findings enhance the understanding of the IL-1 family in the tumor microenvironment and highlight the role of IL-37 in harnessing antitumor immunity
.
In addition, a newly defined inhibitor of the cancer immune cycle, IL-37/SIGIRR, was established as a therapeutic target for colorectal cancer
.
Reference message: https://
.
The molecular mechanism and function of IL-37 in colorectal cancer (CRC) have been elusive
.
On January 20, 2022, Li Jiong and Teng Xiu of Sichuan University jointly published an online article entitled "Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction" in Signal Transduction and Targeted Therapy (IF=18).
, which found that IL-37 transgenic (IL-37tg) mice were highly susceptible to colitis-associated colorectal cancer (CAC) and had a significantly increased colonic tumor burden
.
However, IL-37 is dispensable for intestinal mutagenesis, CRC cell proliferation, apoptosis and migration
.
Notably, IL-37 suppressed protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models
.
IL-37-induced dysfunction antagonizes IL-18-induced CD8+ T cell proliferation and effector function, which is dependent on SIGIRR (single immunoglobulin interleukin 1 receptor-related protein)
.
Finally, this study observed that IL-37 levels were significantly elevated in CRC patients, positively correlated with serum CRC biomarker CEA levels, but negatively correlated with CD8+ T cell infiltration in CRC patients
.
Taken together, our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivating cytotoxic T cells and establish a newly defined suppressor IL-37/SIGIRR in the cancer immune cycle as a treatment for CRC.
target
.
Colorectal cancer is the leading cause of morbidity and mortality worldwide
.
CD8+ cytotoxic T lymphocytes (CTL) are the first immune cells to attack cancer
.
Several studies have determined the density of CD8+ CTLs at the tumor and invasive margins to assess the risk of recurrence in CRC
.
CD8+ CTL infiltration may serve as an independent predictor of favorable survival outcomes in CRC patients
.
CD8+ CTL infiltration is highly responsive to immune checkpoint blockers
.
These findings suggest that CD8+ CTLs are key defenders of CRC
.
CD8+ CTLs kill tumor cells mainly through IFN-γ-mediated or perforin-mediated mechanisms
.
IFN-γ, a CD8+ CTL-derived cytotoxic cytokine, can initiate tumor cell apoptosis by activating the JAK-STAT1-caspase3 cascade
.
The mechanism of perforin-mediated tumor killing is achieved through degranulation of CD8+ CTLs, such as the release of degranulated cargoes, including the cytotoxic proteins perforin and granzymes
.
Perforin promotes the formation of transmembrane pores, leading to the entry of granzymes into tumor cells and triggering apoptosis
.
Cytokines, as secreted proteins, can provide key cues to immune cells, so they are attractive candidate targets for cancer immunotherapy
.
IL-18, a member of the IL-1 family, drives MyD88–IRAK4–JNK signaling through a heterodimeric receptor composed of IL-18Rα and IL-18Rβ subunits
.
Previous studies reported that IL-18 synergized with IL-12 to stimulate the production of the cytotoxic cytokine IFN-γ in CD8+ T cells
.
Recombinant IL-18 has previously been observed to inhibit tumor progression in preclinical models of CRC
.
In addition, recombinant IL-18 has good safety and good tolerability in clinical trials as an anticancer drug
.
These findings redefine the critical role of IL-18 as an antitumor cytokine that fundamentally alters the immune tumor microenvironment
.
Interleukin 37 (IL-37), a new member of the IL-1 family, acts as a recently discovered inhibitor of IL-18, interfering with IL-18-dependent inflammatory factors (TNF-α, IL-18) in renal tubular epithelial cells -1β and IL-6)
.
Previous studies have demonstrated that a tripartite complex consisting of IL-37, SIGIRR and IL-18Ra is essential for the function of IL-37
.
SIGIRR is an orphan receptor and overexpression of SIGIRR inhibits IL-18 signaling in Jurkat and HepG2 cells
.
These findings suggest that SIGIRR may play a critical role in the inhibition of IL-18 signaling by IL-37
.
IL-37 monitors innate immunity and emerges as a key regulator of acquired immunity
.
Schematic diagram of the article (image from Signal Transduction and Targeted Therapy) IL-37 attenuates Th1 responses but promotes the production of Th2 cytokines (IL-13 and IL-4) in ConA, leading to liver injury
.
IL-37 stimulation increased the proportion of Tregs in subjects with infectious diseases and allergies
.
These findings suggest that IL-37 is an important regulator of T cell immune responses
.
Considering the anti-inflammatory properties of IL-37, IL-37 has been found to affect the development of some cancers, such as non-small cell lung cancer, hepatocellular carcinoma, cervical cancer, and colon cancer
.
However, the immunological roles and functional mechanisms of IL-37 remain elusive in the tumor microenvironment
.
Specifically, the role of IL-37 on CD8+ CTL tumor immune surveillance is unclear
.
Discovery and understanding of key molecules and biological processes will provide valuable guidance for developing effective cancer therapies
.
Many IL-1 family members exhibit crucial regulatory roles in antitumor immune responses, thereby affecting tumor immune escape
.
The functional mechanism of the novel IL-1 family member IL-37 in the tumor microenvironment is unclear
.
Here, the study demonstrates that the anti-inflammatory cytokine IL-37 can act as a key inducer of dysfunctional cytotoxic CD8+ T cells that promote colitis-associated carcinogenesis
.
Furthermore, this study shows that IL-37 antagonizes IL-18-induced cytotoxic activity of CD8+ T cells through its inhibitory receptor SIGIRR
.
These findings enhance the understanding of the IL-1 family in the tumor microenvironment and highlight the role of IL-37 in harnessing antitumor immunity
.
In addition, a newly defined inhibitor of the cancer immune cycle, IL-37/SIGIRR, was established as a therapeutic target for colorectal cancer
.
Reference message: https://
