Cell: New target for cancer immunotherapy - SerpinB9

Serpins are involved in regulating many important life processes in the body.
Previous studies have shown that SerpinB9 (Sb9) protects tumor cells from apoptosis induced by granulase B (GrB), a physiological inhibitor of GrB that causes apoptosis when delivered to target cells by cytotoxic lymphocytes, but this protective effect requires comprehensive analysis in in vivo studies.
a new study published in Cell on November 25th, researchers from Harvard Medical School, the Stem Cell Institute and others found that SerpinB9 has the potential to combine tumor ablation, tumor micro-environment (TME) regulation and immunotherapy.
researchers screened a specific Sb9 small molecule inhibitor that effectively controls tumor growth, has no off-target effect, and has no significant toxic effect.
Source: Cell In this study, researchers observed expressions of Sb9 and GrB in a variety of tumors in humans and mice (primary melanoma, breast cancer, and lung adenocarcinoma).
and Sb9 inhibits GrB through the classic serine protease inhibitor mechanism, resulting in the production of the SDS resistance 62 kDa Sb9-GrB complex in mouse melanoma cells (B16).
: Cell researchers using the CRISPR/Cas9 system destroyed the SERPINB9 gene and found that knocking out Sb9 had no effect on the proliferation of B16 cells, but led to a 2x increase in GrB activity and a 2.3x increase in GrB-induced specific apoptosis, suggesting that Sb9 was involved in protecting tumors from GrB-induced apoptosis.
: Cell To explore the role of Sb9 in tumor progression and metastasis in the body, researchers injected wild type (WT) and B16 cells that knocked out Sb9 into mouse models.
On the 27th day after implantation, Sb9-missing tumors were about four times smaller than tumors in the WT group, and in mice with tumor Sb9-missing groups, the medium survival time (MST) of the tumor Sb9-missing group was significantly longer than that of tumor mice in the WT group.
source: Cell However, the researchers did not observe differences in Treg, TAM (M1 and M2) and MDSC levels between WT and tumor cells that knocked out Sb9, suggesting that the expression of tumor Sb9 had little effect on the proportion of immunosuppressive cell populations in TME.
levels of melanoma cells in the tumor drain lymph nodes (TDLN) decreased, proving that the metastasis of Sb9 missing tumors was also reduced.
source: Cell above is the performance of Sb9 missing tumor cells, the researchers then studied the effects of Sb9 over-expression on tumors, after the expression of Sb9 B16-Sb9 plus through the injection into mice, they found that compared to the WT group, B16-Sb9 plus tumors grow significantly faster 21 days after implantation.
: Cell Next, the researchers knocked out Sb9 in mice and found that tumors in mice with Sb9 deficiency grew more slowly and had a significantly longer medium survival time than in WT mice.
In addition, when both the tumor and the host are missing Sb9 (Sb9 KO/Sb9 KO), the tumor development can be prevented to the greatest extent, and the ratio of the effect CD8 T cells in the tumor micro-environment to Treg, effect memory CD8 T cells and Treg cells is significantly higher than that of WT/WT group, and the TM and MDSC of Sb9 KO group is significantly lower than that of WT/WT group.
Source: Cell researchers concluded that the absence of Sb9 in Treg, TAM, and MDSC exposed them to GrB-mediated killing in TME, eventually leading to the recovery of the anti-tumor immune response and the suppression of tumor progression.
3034 is a small molecular compound with excellent properties that can be directly combined with Sb9, which can reduce the expression of the B16 cell Sb9-GrB complex by dose dependence.
In in vivo experiments, after 3034 injections, the immunity of mouse tumors was significantly improved, the B16 tumor implanted on the abdominal side was significantly reduced, and the levels of immunosuppressive Treg, TAM and MDSC were significantly reduced.
: Cell tested the efficacy of 3034 in human-derived melanoma mouse models to assess whether the anti-tumor effect of 3034 could be extended to human patients.
showed that 3034 significantly reduced tumor size compared to the control group.
and 3034 can induce GrB-mediated apoptosis in B16 cells, the activity of GrB increased in 3034 treated B16 cells, and 3034 has no off-target effect and no significant toxic effect.
: Cell Overall, this study highlights the importance of Sb9 in inhibiting tumor metastasis, which may be a more effective and safer treatment than immunosuppression.
, however, more research is needed in the future to express and optimize the affinity and efficacy of Sb9 inhibitors combined in the body.
: Liwei Jiang, et al. Direct Tumor Killing and Immunotherapy through Anti-SerpinB9 Therapy. Cell (2020) Source: Medical Rubik's Cube Pro