Cell: Cancer’s accomplice, new research has found that secreted gel protein can inhibit the body’s cancer immunity

How does the human body fight tumor formation? The human immune system includes a variety of immune cells, among which type 1 conventional dendritic cells (cDC1) are essential for effective anti-tumor immunity
.

It can recognize tumor antigens and trigger the anti-tumor immune effect of CD8+ T cells

The interference of cDC1 recruitment in cancer has become a means to evade the body's immunity, and increasing the recruitment, survival, expansion and functional activity of cDC1 in the tumor microenvironment (TME) has anti-tumor effects
.

Today, interventions for tumor immune control have shown good application prospects, and there are also researches on interventions in this pathway

On June 2, 2021, the international academic journal "Cell" published an online study titled "Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and cancer immunity" by the Caetano Reis e Sousa team of the Francis Crick Institute in the United Kingdom
.

This study revealed that the endogenous factor sGSN promotes tumor immune evasion by inhibiting the presentation of tumor-associated antigens by cDC1

The researchers proposed that cDC1 expresses a high level of c-type lectin receptor DNGR-1 (also known as CLEC9A), which can bind to F-actin exposed on the surface of necrotic cells to promote the cross-transmission of dead cell antigens
.

The human body contains two abundant actin binding proteins (ABP), secreted gel protein (sGSN) and Gc globulin, which can inhibit the recognition of necrotic cells by cDC1, thereby inhibiting tumor immunity

Researchers found that fetal calf serum (FCS) has an inhibitory effect on the binding of DNFR-1 to F-actin, while FCS after F-actin treatment and high-speed centrifugation loses this function
.

Researchers believe that this is related to ABP in the serum

Subsequently, the researchers constructed a sGSN-/- mouse model and found that the serum of sGSN-/- mice could not inhibit the binding of DNGR-1 to F-actin.
After adding recombinant sGSN, the inhibition was restored, and another ABP— -Gc globulin does not have this inhibitory ability
.

Inhibition of sGSN on the binding of DNGR-1 and F-actin

Inhibition of sGSN on the binding of DNGR-1 and F-actin.
Inhibition of sGSN on the binding of DNGR-1 and F-actin

Researchers speculate that sGSN-/- mice have increased anti-tumor CD8+ T cell responses
.

To verify this point of view, they constructed LA-OVAmCherry MCA-205 tumors in sGSN-/- mice.

Loss of sGSN impairs tumor growth and enhances response to immunotherapy

Deletion of sGSN impairs tumor growth and enhances response to immunotherapy.
Deletion of sGSN impairs tumor growth and enhances response to immunotherapy

Combining the results of the above animal experiments, the researchers speculate that in humans, certain cancers are also related to sGSN
.

They analyzed the information of 10 cancers (skin, liver, breast, lung, pancreas, prostate, low-grade glioma (LGG), head and neck, stomach and colorectal cancer) in the Cancer Genome Atlas (TCGA) The results show that low sGSN levels are correlated with the survival of patients with high CLEC9A expression

Subsequently, the researchers tested the expression of F-actin binding proteins (FABPs) in patients with LIHC, HNSC and STAD, and further grouped patients according to the level of sGSN transcription in the tumor
.

The results showed that low sGSN combined with FABP mutation overall survival rate of the three cancers is correlated

Low sGSN level is correlated with survival of patients with high CLEC9A expression

Low sGSN level is correlated with survival of patients with high CLEC9A expression

In general, this study clarified that sGSN is a previously undiscovered tumor immune evasion-related factor
.
sGSN inhibits the activity of DNGR-1 and at the same time inhibits the DNGR-1-dependent cross-presentation of dead cell-related antigens in tumors by cDC1, thereby promoting cancer immune evasion
.

Therefore, transient targeting of the interaction between sGSN and F-actin may be a safe and effective tumor immunotherapy strategy
.

Original source:

Original source:

Evangelos Giampazolias Oliver SchulzKok Haw Jonathan Lim, et al.
Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and cancer immunity .
Cell, 2021.

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