*For medical professionals only
Who lives in the big pineapple in the deep sea?
SpongeBob SquarePants!
Cheese head brown pants!
Today's protagonist is none other than the star of the sea creatures, the little sponge.
The sponge is a very primitive and unique multicellular aquatic invertebrate in the ocean, which has no real tissues and organs, and its body is made up of many tiny holes that allow the current to pass through and thus capture tiny food particles. Due to their unique physiology, chemical composition, and important role in marine ecosystems, sponges are invaluable in the field of drug development and marine biology.
Recently, Liu Sanhong from Shanghai University of Traditional Chinese Medicine and Zhang Weidong from the Naval Medical University published a paper in the journal Cell Reports Medicine, pointing out that Benzosceptrin C (BC), a natural extract of sponges, can provide wonderful new ideas for cancer immunotherapy [1].
For the first time, the research team found that BC can promote the degradation of PD-L1 in tumor cells through the lysosomal pathway, thereby reducing the expression level of PD-L1 and enhancing T cell-mediated anti-tumor immunity.
The efficacy of BC alone is comparable to that of PD-L1 inhibitors, and BC can exert a synergistic effect when used in combination with CTLA-4 inhibitors, which can more effectively inhibit the growth of colorectal cancer tumors without obvious toxicity.
Screenshot of the paper
During tumor development, immune checkpoint proteins such as PD-L1 expressed by tumor cells bind to the corresponding ligands on immune cells and exert immunosuppressive effects, resulting in T cells being unable to recognize tumor cells and help them complete immune evasion. Therefore, scientists have tried their best to manipulate PD-L1 to maximize the assistance of the immune system to "open its eyes" and remove tumor cells.
In this study, the research team screened 300 natural compounds and found that benzosceptrin C (BC) had the effect of a PD-L1 inhibitor.
BC is a pyrrolizimidazole marine alkaloid isolated from agasa sponges with a novel benzocyclobutane backbone [2,3]. The research team found that BC was able to significantly reduce PD-L1 expression levels in human colorectal cancer cells in a time- and concentration-dependent manner, reduce PD-L1 transport to the plasma membrane, and exhibit little toxicity to cells at concentrations of 0-10 μM.
BCs with PD-L1 inhibitor activity are found from the library of natural compounds
Further in vitro experiments and validation results showed that BC promoted T cell activation and enhanced T cell toxicity by down-regulating the expression of PD-L1 on the surface of tumor cells and weakening its ability to bind to PD-1 on the surface of T cells.
From a mechanism point of view, BC forcibly recovered PD-L1.
Palmitoylation is a reversible protein modification that can regulate physiological processes such as protein trafficking, stability, and cell membrane binding. Here, the research team found that palmitoylation of PD-L1 by palmitoyltransferase DHHC3 hindered the ubiquitination of PD-L1, thereby preventing PD-L1 on the cell membrane from being recycled and sent to lysosomes for degradation by a membrane-encapsulated vesicle structure called endosomes.
However, BC can inhibit its palmitoylation activity by binding to DHHC3, which promotes the eventual degradation of PD-L1 by lysosomes.
Mechanism diagram
Due to the extremely low natural content of BC in sponges, it is difficult to obtain enough natural extract, and the research team successfully completed the synthesis of BC in the laboratory and used it to treat a mouse model of colorectal cancer.
The results showed that once-daily BC treatment for 16 days could significantly inhibit tumor progression and promote anti-tumor immunity in colorectal cancer mice. Compared with the control group, the inhibition efficiency at 25 mg/kg and 50 mg/kg was 30.4% and 43.1%, respectively, and the tumor size and weight were reduced, and the levels of apoptosis factors in BC-treated colorectal cancer mice were up-regulated, the levels of immunosuppressive molecules PD-L1 and FOXP3 were reduced, and the tumor markers were significantly reduced.
The effect of BC in inhibiting colorectal cancer tumor growth was abrogated in T-cell-deficient mice, suggesting that BC exerts anti-tumor activity by activating T-cell immunity.
BC therapeutic effect
In terms of safety, BC did not cause significant changes in the body weight of the mice, none of the mice died during the treatment, and there were no significant toxicity in the heart, liver, spleen, lungs or kidneys of BC-treated mice.
Similarly, the targeted blockade of the PD-1/PD-L1 pathway, the research team compared the efficacy of BC and PD-1 inhibitors in a mouse model of colorectal cancer, and the results showed that the anti-tumor strength of the two was comparable, and there was no synergistic effect when used together.
The research team also compared BC to a CTLA-4 inhibitor, a therapy that targets another immune checkpoint protein.
The results showed that the anti-tumor effects of BC and CTLA-4 inhibitors were similar, and the growth rate, volume and weight of colorectal cancer mice were further reduced when the two were treated together, the number of CD8+ T cells and granzyme B levels were increased compared with the treatment alone, and the accumulation of myeloid suppressor cells and regulatory T cells was reduced compared with the treatment alone. These results suggest that BC and CTLA-4 inhibitors have a synergistic effect in inhibiting tumor progression and improving tumor microenvironment.
PD-L1 inhibitors, BC, CTLA-4 inhibitors alone or in combination with treatment
Finally, the research team used the data of 6 colorectal cancer patients and the TCGA database to analyze, and the results were as expected, the expression levels of DHHC3 and PD-L1 in tumor tissues were higher than those in adjacent tissues, and the expression of DHHC3 and PD-L1 was positively correlated. These results suggest that DHHC3-mediated palmitoylation modification is required for the stability of PD-L1 in colorectal cancer.
There was a positive correlation between DHHC3 and PD-L1 expression
All in all, Liu Sanhong, Zhang Weidong et al. revealed for the first time that Benzosceptrin C, a natural extract of marine sponge, actually has the effect of PD-L1 inhibitors, and it also plays a synergistic role when used in combination with CTLA-4 inhibitors. Moreover, unlike antibody therapy, which may cause immune-related adverse events, lower doses of benzosceptrin C do not cause significant toxicity, showing great potential clinical application value.
Little sponge, to open up a new world for anti-tumor immunotherapy!
Bibliography:
[1]https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(23)00574-8
[2] Tilvi, S., Moriou, C., Martin, M.T., Gallard, J.F., Sorres, J., Patel, K., Petek, S., Debitus, C., Ermolenko, L., and Al-Mourabit, A. (2010). Agelastatin E, agelastatin F, and benzosceptrin C from the marine sponge Agelas dendromorpha. J. Nat. Prod. 73, 720–723.
[3]https://www.shutcm.edu.cn/2024/0119/c6529a158201/page.htm
The author of this article丨Zhang Aidi