How does the human body fight against tumor formation? The human immune system includes many kinds of immune cells, among which type 1 conventional dendritic cells (cDC1) are essential for effective anti-tumor immunity. It can recognize tumor antigen and induce the anti-tumor immune effect of CD8 + T cells. When cDC1 is absent, CD8 + T cell-driven tumor immunity will subside, and the therapeutic effect of CD8 + T cell activator and immune checkpoint blocking inhibitor will also decline. Therefore, cDC1 abundance and CD8 + T cell infiltration are closely related to the response of cancer patients to anti-tumor therapy and overall survival rate.
Interference of the recruitment of cDC1 in cancer has become a means to escape the body’s immunity, and increasing the recruitment, survival, expansion, and functional activity of cDC1 in the tumor microenvironment (TME) has an anti-tumor effect. Up to now, the intervention of tumor immune control has shown a good application prospect, and the intervention of this pathway has also been studied.
Cell published a study entitled “Secret gelsolin inhibitors DNGR-1-dependent cross-presentation and cancer immunity” by Caetano Reis e Sousa team of Francis Crick Institute. This study revealed that the endogenous factor SGSN promotes tumor immune evasion by inhibiting the presentation of tumor-associated antigen by cDC1.
The researchers suggest 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 and promote the cross-transmission of dead cell antigens. The human body contains two kinds of abundant actin-binding proteins (ABP), that is, secreted gel protein (sGSN) and Gc globulin. They can inhibit the recognition of cDC1 on necrotic cells and inhibit tumor immunity.
The researchers found that fetal bovine serum (FCS) inhibited the binding of DNGR-1 to F-actin, but FCS treated with F-actin and centrifuged at high speed lost this function. The researchers believe that this is related to ABP in serum. On the contrary, F-actin treated with SGSN could not bind to DNGR-1, which proved that SGSN inhibited the binding of DNGR-1 to F-actin from two directions.
Subsequently, the researchers constructed the 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 inhibitory effect was restored, while another ABP Gc globulin did not have the inhibitory ability.
The researchers speculated that the anti-tumor CD8 + T cell response of SGSN – / – mice was increased. To test this view, they constructed la-ovamcherry MCA-205 tumor in SGSN – / – mice. The results showed that the tumor growth in SGSN – / – mice were significantly smaller and more sensitive to cancer immunotherapy. However, whether DNGR-1 is present or not, the absence of SGSN will not affect the activation of cDC1, and the increase of therapeutic responsiveness is mainly related to CD8 + T cell.
Combined with the results of the above animal experiments, the researchers speculate that some cancers in the human body 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 showed that low SGSN levels were associated with survival in patients with high CLEC9A expression.
Then, they detected the expression of F-actin binding proteins (FABPs) in patients with LIHC, HNSC, and STAD, and further grouped the patients according to the SGSN transcription level in the tumor. The results showed that the overall survival rates of three cancers with low SGSN and FABP mutations were correlated.
Overall, this study confirmed that SGSN is a previously unknown tumor immune evasion-related factor. SGSN inhibited the activity of DNGR-1 and the DNGR-1 dependent cross-presentation of cDC1 to dead cell-associated antigens in tumors, which promoted the immune evasion of cancer.
Therefore, transient targeting interaction between SGSN and F-actin may be a safe and effective strategy for tumor immunotherapy.
Evangelos Giampazolias, Oliver Schulz, Kok Haw Jonathan Lim, et al. Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and cancer immunity. Cell. https://doi.org/10.1016/j.cell.2021.05.021