If you are an immune cell ready to fight cancer, you’d better eat some breakfast. Because the tumor microenvironment is a harsh place, and tumor cells are always ready to make you exhausted.

 

Improvement of highly specific immune fighter in vivo: The ability of T cells to attack tumors has achieved clinically significant advances in tumor immunotherapy. However, this method is only effective in 10-30% of patients. One reason is the “T-cell exhaustion”. This is because T cells are stimulated repeatedly in the tumor microenvironment and eventually lose their ability to kill tumors. New research from the University of Pittsburgh School of Medicine and the UPMC Hillman Cancer Center has shown that targeted therapy that prevents or reverses this metabolic depletion can enhance immunotherapy and may help more people.

 

 

The study was recently published in Journal of Experimental Medicine, which led to these discoveries by revealing the working principle of a protein called 4-1BB on the surface of T cells. 4-1BB is a co-stimulatory factor that T cells activate when fighting infection, but the environment inside the tumor inactivates it. Previous studies have found that activating 4-1BB can help T cells to replicate and maintain for a long time, but it is unclear how it works.

 

“What we have discovered is that the 4-1BB’s effect can be completely chalked up to how it alters the metabolism of T cells. In a sense, the activated 4-1BB keeps the T cells in a full state and therefore can continue to fight,” said Dr. Greg M. Delgoffe, Ph.D., an associate professor of immunology at the Pitt’s School of Medicine and an investigator at the UPMC Immune Transplant and Therapy Center.

 

In laboratory-cultured mouse T cells, the researchers discovered that a protein antibody can activate 4-1BB, leading to an increase in the number and fusion of mitochondria in T cells.

 

“The activated 4-1BB increases the energy supply of T cells, so these cells can completely release their killing capacity as needed,” said Ashley Menk, a researcher at Delgoffe Laboratories and the author of the study.

 

However, drugs that activate 4-1BB were not successful in clinical trials. To address this issue, the researchers tested whether activation of 4-1BB could improve the efficacy of both immunotherapies: a checkpoint inhibitor drug that inhibits PD-1 protein on T-cells and a cellular therapy that uses engineered T cells to recognize cancer cells.

 

When tested in a mouse model of melanoma which typically had low response rates for both therapies, the combination resulted in much better outcomes.

 

“Although activating 4-1BB solves the energy problem, it does not solve the immunological problem, which is exactly what checkpoint inhibitors or cellular therapies are great at. Therefore, we found that the combination of the two is superior to the simple addition of the two therapies.” Delgoffe said.

 

Interestingly, the researchers also found that using 4-1BB activator in advance activates 4-1BB for a short period of time. The subsequent use of PD-1 immunotherapy has the same effect as the two therapies, which may reduce 4-1BB activation-related side effects.

 

Researchers are testing the efficacy of combination therapies in human tumor models and will conduct clinical trials in the future.

 

 

 

Reference

Greg M. Delgoffe et al. 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses.Journal of Experimental Medicine. DOI: 10.1084/jem.20171068