In a new study published in Nature Immunology titled, “Engineering NK and T cells with metabolite-sensing receptors to target solid tumors”, researchers from Stanford University have developed an approach that equips specific immune cells with metabolite-sensing receptors that recognize byproducts of cancer cells to trigger migration toward the tumor. The approach differs from CAR T-cell therapy, which recognizes proteins tethered to the surface of the cancer cell.
“We found that when we equip immune cells with receptors that sense metabolites released by cancer cells, they can sense the tumor, migrate toward it, infiltrate it and control tumor growth, which markedly enhances the survival of mice with human breast and ovarian cancers,” said Livnat Jerby, PhD, assistant professor of genetics and corresponding author of the study.
Research suggests that CAR T cells are prone to excessive signaling and become exhausted before they can eliminate solid tumors. In addition, identifying molecular targets on solid tumors that are specific cancer cells and not found on normal tissue remains an ongoing challenge.
“There have been many studies trying to overcome T cell exhaustion,” Jerby said. “But our study supports and was driven by the notion that the problem with treating solid tumors is also a spatial issue. Too few T cells are getting into the tumor.”
The authors compared the RNA levels between breast cancer tumors and blood samples from 22 breast cancer patients to identify genes that were highly expressed in immune cells present in the tumor. They also mined a database of RNA expression levels in natural killer (NK) cells in more than 700 patients and 24 types of cancer, and identified 256 candidate genes for functional studies.
The search revealed many receptors that recognize bioactive, chemoattracting metabolites that have not undergone extensive study in the context of cell engineering and tumor immunology.
“We saw the same hits, time after time in different model systems with different screens and different experimental settings. It was quite striking,” Jerby continued.
Jerby and colleagues found that NK cells that had been engineered to express one of six genes were consistently more successful at infiltrating breast and ovarian tumors in animal models, migrating specifically to cancer cells and the factors they release. As these genes encode proteins G-protein coupled receptors (GPCRs), the researchers coined the term tumor-homing GPRs (thGPRs).
These thGPRs are known to recognize and migrate toward specific types of phospholipids, fatty acids and derivatives of cholesterol, which are generated by cancer cells during proliferation. Patient data showed that these metabolites recruit tumor-friendly immune cells, creating an environment that supports tumor growth and resists drug treatment. Jerby says these features can be exploited for cancer diagnostic scans, such as PET imaging, which pinpoints areas in the body with high metabolic activity.
The researchers focused on one of the thGPRs, GPR183, in breast cancer. Engineering NK or T cells to express GPR183 on their surfaces markedly enhanced the ability of the cells to migrate toward cancer cells in laboratory dishes or in mice. Expressing GPR183 on the surface of NK cells, CAR NK cells, CAR T cells and other types of tumor reactive T cells led to significantly improved tumor control and survival of laboratory mice with breast cancer tumors.
Jerby and her lab members are now investigating whether thGPRs can be modified to recognize other tumor metabolites that are not normally chemoattracting as navigation cues. Another therapeutic mechanism seeks to activate immune cells in the presence of tumor metabolites. The team is also moving toward testing the GPR183-engineered cells in clinical trials and identifying other thGPRs for their therapeutic potential.
“To the best of our knowledge, no one has tried to use cancer metabolism, a hallmark of drug resistance and aggressive tumor growth, to attract cancer-killing immune cells to the tumor,” Jerby said. “But our study uncovered the potential of this approach, and the results are quite promising.”
