Novel Immune Checkpoints Could Combat Cancer-Related Immunosuppression, Autoimmune Diseases

New research has identified 3 novel immune checkpoints that could be involved in combating autoimmune diseases and immunosuppression in cancer patients, according to a press release from the University of Connecticut.

Tumor progression is often accompanied by immunosuppression in patients with cancer, resulting in an inability for the body to properly fight pathogens. By contrast, autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, and multiple sclerosis, occur when the immune system overreacts and attacks the body itself.

Both of these reactions are influenced by molecular checkpoints found in immune checkpoints and cancer cells. In immune cells, these checkpoints are intended to prevent the immune system from overreacting and attacking healthy cells, so the checkpoint molecules fail to function properly in autoimmune diseases. In cancer cells, they bind to immune cell receptors and inhibit their function.

Investigators at the University of Connecticut used bioinformatics and gene engineering techniques to create a series of recombinant proteins and antibodies to address concerns for both autoimmune diseases and cancer cells. The investigators noted that there are several FDA-approved medications to produce recombinant proteins that treat autoimmune disease, as well as antibodies to block the inhibitor activity of these checkpoints for cancer patients; however, not all patients respond to these treatments.

Researcher Laijun Lai, MD, identified 3 additional checkpoints involved in these processes: CD300c, ERMAP, and TAPBPL. These checkpoints are found in both immune cells and cancer cells. His bioinformatics approach identified checkpoints that were most likely to be relevant based on genetic and structural similarities to previously identified molecules. Each molecule binds to a specific immune cell receptor to send an inhibitory signal and uses different mechanisms to check immune cell responses.

“The expression patterns of our molecules are different from existing checkpoint molecules and, probably, a different subset of patients will respond to them,” Lai said in the press release.

The investigators then used genetic engineering to develop recombinant proteins from the genetic blueprint of these proteins. Lai demonstrated that these recombinant proteins can successfully suppress T-cell function in animal models of autoimmune diseases.

The group has also developed antibodies that can block the inhibitory activity of these checkpoint molecules. According to the press release, Lai found that the antibodies enhance antitumor immunity and inhibitor tumor growth. The therapies can be combined with existing antibodies for programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), or used on their own for patients who do not respond to those treatments.

“Our antibodies against these checkpoint molecules have the potential to be used in the treatment of cancer patients who are resistant to the anti-PD-1, PDL1, and CTLA-4 antibodies and can also be used in combination with existing antibodies to enhance the antitumor effects,” Lai said in the press release.

REFERENCE

Novel Immune Checkpoints Have Applications for Cancer, Autoimmune Disease Treatment [news release]. University of Connecticut; May 20, 2021. Accessed May 27, 2021. https://today.uconn.edu/2021/05/novel-immune-checkpoints-have-applications-for-cancer-autoimmune-disease-treatment/.