A new strategy to transform immunotherapy for liver cancer

Newswise – In recent years, tumor immunotherapy has become a very promising and much touted cancer approach. It is based on the use of humanized antibodies called immune checkpoint inhibitors (ICI) to block cellular pathways that inhibit the activity of T lymphocytes, a type of cells in the immune system that help protect the body against infections and can help fight cancer.

The best known antibodies are those directed against CTLA-4, PD-L1 and PD-1.

Yet despite encouraging results in the use of immunotherapy to treat certain types of malignant tumors, most cancer patients respond poorly or not at all to treatment using IBI, especially patients with liver cancer.

As a result, researchers looked for ways to improve the effectiveness of immunotherapy, including combining more than one treatment. Several “combination therapies” are currently in clinical trials, but no preclinical data or clear rationale has yet appeared to give credit to the combination therapy approach.

In a new study, published online December 3, 2021 in the journal Hepatology, researchers at the University of California at San Diego, led by senior author Gen-Sheng Feng, PhD, professor of pathology in the School of Medicine and Molecular Biology in the Division of Biological Sciences, demonstrate a proof of principle that liver cancer can be made highly reactive to an immune checkpoint inhibitor known as anti-PD-L1 antibodies using a Synthetic dsRNA molecule dubbed polyIC in tandem to enhance the innate immunity of the liver.

“There are two issues that we need to keep in mind in developing liver cancer immunotherapy,” Feng said. “In general, the tumor microenvironment is generally characterized by immune suppression, otherwise tumors will not grow. Another level of complexity is that the liver is a particularly immuno-tolerant organ constantly exposed to foreign substances from food. Successful immunotherapy must be based on exceeding hepatic immune tolerance and disrupting the immune evasion mechanism in the tumor microenvironment.

To address these issues, Feng and his colleagues generated two murine tumor models, one with tumors growing under the skin and the other with tumors growing in the liver. Both types of tumors were derived from the same colorectal cancer cell line, which allowed researchers to specifically study the role of different tumor microenvironments.

They compared the responses of subcutaneous and hepatic tumors to the same treatment using the anti-PD-L1 antibody, the polyIC molecule, or a combination of the two. They found that polyIC or anti-PD-L1 monotherapy effectively suppressed subcutaneous tumor growth, according to previous public reports. No monotherapy produced a significant therapeutic effect on tumors growing in the liver of mice.

But Feng and his colleagues found that the combination of the two reagents showed remarkably synergistic effects in inhibiting liver tumors, even better than in subcutaneous tumors. Their analyzes suggest that this was largely due to the efficient strengthening of the cytotoxic CD8 T lymphocyte subpopulation in the liver, simultaneously activating innate immune cells by polyIC and blocking the inhibitory pathway in the T lymphocytes with the anti- antibody. PD-L1.

“The detailed molecular and cellular mechanisms underlying the synergistic effect of this combination have yet to be deciphered,” said Feng. “The reason we’re excited is that the data suggests a possibility that liver cancer may become very responsive to immunotherapy, as long as a way can be found to overcome the immunosuppressive liver environment. There is a bright future for patients with liver cancer to benefit from immunotherapy. “

The study, the authors noted, also raised a caveat regarding immunotherapy research of the subcutaneous tumor model. “This model was used in the pioneering work for cancer immunotherapy,” said Feng, “and it remains the most frequently used animal tumor model in cancer immunology. However, our studies have shown value. limited of the subcutaneous tumor model in dissecting the unique microenvironment of the liver tumor. “

Co-authors include: Bing Xin, Meixiang Yang, Panyisha Wu, Li Du, Hester Deng, Enfu Hui, all at UC San Diego.

Funding for this research comes, in part, from the National Cancer Institute (grants R01CA236074, R01CA239629, R37CA239072), the National Institutes of Aging (P01AG073084) and the Krueger v. Wyeth.


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