Using a matrix metalloproteinase (MMP) inhibitor with cryoablation to treat hepatocellular carcinoma (HCC) improved CD8 T-cell immune response in a mice model.
The findings of abstract No. 171, “The Effect of Anti-MMP-9 as a Potential Modulator of the Post-Cryoablation Anti-Tumor Immune Response in HCC,” will be presented Monday, June 13, at 4:12 p.m. as part of Scientific Session 27 Combination and Comparison IO Studies.
In the past 5 years, several immunotherapies have been introduced to treat advanced liver cancer. However, the response rate continues to be limited to 20–30%. Contributing factors may be dysfunctional tumor-immune system interactions that lead to immune evasion by generating an immunosuppressive tumor microenvironment. Yale University researchers set out to explore how cryoablation alone versus combined with MMP inhibitors may reverse the immunoevasive tumor microenvironment and amplify ablation-induced local antitumor immune responses.
They decided to combine the use of an MMP-9 inhibitor with cryoablation, an ablation technique not recommended as first-line treatment for HCC, according to presenter Annabella Shewarega, who spent the past year as a research fellow in the Yale Interventional Oncology Research Lab. Ms. Shewarega is a sixth-year medical student from Germany. (Medical school in Germany is 6 years and 3 months.)
Matrix metalloproteinases are a group of enzymes known to play a role in invasion and metastasis of human cancers, so “our goal was, after ablating the tumor, to inhibit these enzymes and evoke greater tumor-specific immune responses,” she said.
Typically, mice receiving cryoablation for HCC usually have a high infiltration of macrophage and unchanged T-cell counts, showing that the mice immune systems did not fight the cancer after ablation. But in this study, inhibition of MMP-9 after cryoablation in 36 mice reduced tumor-associated macrophage recruitment (CD68) and M2 polarization (CD206) compared to cryoablation alone. In addition, the treatment increased CD8+ T cell infiltration in the HCC tumor microenvironment compared to all control groups.
“The reason we chose cryoablation instead of radiofrequency ablation or microwave ablation is that cryoablation stands out in its superiority to preserve the native antigen structures,” Ms. Shewarega said. “All ablation techniques result in release of tumor antigens to the host’s immune system, eliciting tumor-specific immune response. But cryoablation preserves the native antigen structures, whereas the other heat-induced ablation treatments usually denature those antigens.
“We believe that cryoablation can induce a better tumor-specific immune response so that, in coalition, various immunotherapies are more amenable for cryoablation,” she continued.
Ms. Shewarega would like to see this combination treatment investigated further. She added: “I believe MMP-9 inhibition is not the only immune modulatory treatment that could improve immune cell penetration of tumors unaffected by ablation. For instance, [we could study] other immunotherapies that are already in use in humans and see whether the combination with cryoablation enhances those antitumor immune responses.”
