Researchers at Massachusetts General Hospital (MGH) have found that interferon gamma receptor (IFNgR) signaling is essential for the susceptibility of CAR-T cell immunotherapy to kill malignant gliomas. The same phenomenon has been observed in other solid tumors. The findings may partially explain why liquid and solid tumors respond very differently to CAR-T cell therapy.
Chimeric antigen receptor (CAR) is a synthetic molecule that specifically commands T cells of the immune system to recognize and adhere to a target or antigen. CARs are able to recognize targets on the surface of tumor cells. Although CAR-T therapy has revolutionized the treatment of hematological diseases such as leukemia and lymphoma, it has not translated into similar success in solid tumors.
To determine the resistance pathway in solid tumors, researchers led by Dr. Marcela Maus, director of the Cellular Immunotherapy Program at Massachusetts General Hospital Cancer Center, developed a genome-wide CRISPR knockout to screen gliomas.
Lead author Dr. Rebecca Larson explained: “Through CRISPR screening, we are able to interrogate the entire genome in a fully fair way, in a pooled format, rather than looking for one or two genes of interest at a time.” This allows researchers to see which genes are lost and determine the resistance mechanisms used by solid tumors to evade CAR-T cell therapy. In this study, they applied selective pressure with CAR to each barcoded cell on the screen.
“Then, we sequence these cells and can see which tumor cells are alive and then tell us which genes are knocked out.”
When Larson and colleagues applied this screen to a variety of glioblastoma cell lines, including several from patients, they unexpectedly found that loss of genes in the interferon gamma signaling pathway made them resistant to killing by CAR-T cells. This means that those genes associated with interferon are necessary for tumors to die in front of CAR, something we did not know before, and we did not expect,” Larson added.
The same resistance pattern was found in knockout mouse models in vivo. Further studies of other solid tumor types, including pancreatic, ovarian, and lung cell lines, showed the same results: the resistance to CAR-T cell therapy stems from the loss of interferon pathway genes.
“We found that CAR-T cells did not bind to glioblastoma cells that lack interferon signaling,” Larson explained. Although interferon does not directly kill cancer, it makes tumor cells stickier. “In this way, CAR-T cells can better combine with them and eliminate cancer cells.”
In contrast, the researchers observed no effect of the interferon pathway on the sensitivity of leukemia, lymphoma, or multiple myeloma to CAR-T cell therapy. “In fact, we can see different responses of solid and liquid tumors to CAR-T cell therapy, which is very helpful in how we design future treatments.”
With the deepening of research, the findings provide researchers with clinical opportunities in two aspects. First, enhancing T cell/tumor cell binding interactions by targeting the interferon pathway may yield better responses using CAR-T cell therapy in solid tumors. Second, blocking the pathway in liquid tumors may help to reduce the well-known toxicity of CAR-T cell therapy, namely cytokine release syndrome. Although CAR-T cell therapy has a cure rate of more than 40% for certain liquid tumors in some cases, toxicity is a real problem, and inhibition of interferon γ in these cancers may maintain efficacy but reduce toxicity.”
