Immune checkpoint inhibitors are the most used immunotherapies. They work by recognizing and blocking proteins that cancer cells use to hide from the immune system. However, cancer cells that don’t have these proteins use different ways to hide. Since patients with these cancers don’t respond to immune checkpoint inhibitors, researchers are seeking new ways to develop immunotherapies with different targets. Now, researchers from Osaka University have discovered that tetracycline antibiotics help the immune system find cancer cells in a way that is different from current immunotherapies.
The results of their study were published in the Journal for ImmunoTherapy of Cancer in an article titled, “Tetracyclines enhance anti-tumor T cell immunity via the Zap70 signaling pathway.”
Tetracycline antibiotics have been used to treat patients with infectious diseases for many years. Now, these old drugs may point the way to new immunotherapies for cancer patients who currently have few treatment options.
“Cancer immunotherapy including immune checkpoint inhibitors is only effective for a limited population of patients with cancer,” the researchers wrote. “Therefore, the development of novel cancer immunotherapy is anticipated. In preliminary studies, we demonstrated that tetracyclines enhanced T-cell responses. Therefore, we herein investigated the efficacy of tetracyclines on antitumor T-cell responses by human peripheral T cells, murine models, and the lung tumor tissues of patients with non-small cell lung cancer (NSCLC), with a focus on signaling pathways in T cells.”
The researchers investigated the tetracycline antibiotic minocycline in blood and tumor tissue from lung cancer patients.
“The cytotoxicity of peripheral and lung tumor-infiltrated human T cells against tumor cells was assessed by using bispecific T-cell engager (BiTE) technology (BiTE-assay system),” the researchers noted. “The effects of tetracyclines on T cells in the peripheral blood of healthy donors and the tumor tissues of patients with NSCLC were examined using the BiTE-assay system in comparison with anti-programmed cell death-1 (PD-1) antibody, nivolumab. T-cell signaling molecules were analyzed by flow cytometry, ELISA, and qRT-PCR. To investigate the in vivo antitumor effects of tetracyclines, tetracyclines were administered orally to BALB/c mice engrafted with murine tumor cell lines, either in the presence or absence of anti-mouse CD8 inhibitors.”
“We found that minocycline enhanced the antitumor activity of T lymphocytes by targeting galactin-1, which is an immunosuppressive protein produced by cancer cells,” explained lead author Mari Tone.
The team found that galactin-1 helps cancer cells hide from the immune system by preventing cytotoxic T lymphocytes from reaching the tumor. After treatment with tetracycline, galactin-1 was no longer able to stop the T lymphocytes from attacking the tumor. The researchers believe blocking galactin-1 might be the key to new cancer treatments.
“These antibiotics have a different mechanism of action from immune checkpoint inhibitors and other immunotherapies used to treat cancer,” said corresponding author Kota Iwahori.
The researchers hope their findings will lead to the development of new drugs that target different immune pathways and can help people with cancer, particularly those who don’t benefit from current immunotherapies.
