Significance of MHC-II in Immunotherapy

Patient-specific variations in MHC-II molecules have as much, if not more, of an impact on the mutations that arise in tumors as MHC-I variations, according to new research published in Cell. In addition, MHC-II shows less interpatient variability, but stronger selective effects, when compared with MHC-I.

Previous research has shown that MHC-I molecules play a significant role in shaping the mutational landscape of cancer. In addition, a better understanding of neoantigens may allow for improved immunotherapies, according to the study authors.

MHCs are molecules that communicate the health of a cell to the immune system by presenting peptides for recognition by T cells. MHC class I molecules are expressed on nearly all nucleated cells and show peptides from inside the cell. MHC class II molecules, on the other hand, are expressed on only professional antigen-presenting cells, such as dendritic cells and macrophages, and show peptides that are absorbed from outside the cells.

Lead study author Rachel Marty, of the Division of Medical Genetics at the University of California San Diego in La Jolla, California, said that, until now, the anticancer immune response against mutated peptides of potential immunological relevance has been primarily attributed to MHC-I–restricted cytotoxic CD8+ T cell responses. However, she and her colleagues found that patient-specific and residue-specific PHBR-II scores estimate mutation presentation by MHC-II. In addition, tumors are less likely to harbor driver mutations that bind well to MHC-II.

“For individuals, this means that patient-specific MHC-II variation could impact the mutations that arise in that patient’s tumor. Moreover, frequent mutations in the population must not only be oncogenic, but must also be evading MHC-II binding. Clinically, we need to give MHC-II and CD4 T cells the respect they deserve when developing new immunotherapy approaches,” Marty told Cancer Network.

The researchers constructed models of an individual’s MHC-II genotype to present 1,018 driver mutations in 5,942 tumors. They found that the MHC-II genotype constrains the mutational landscape during tumorigenesis in a manner complementary to MHC-I. These new findings suggest that MHC-II presentation has a central role in tumor evolution.

“Honestly, I was quite surprised by the higher level of MHC-II mutation selection as compared to MHC-I,” said Marty. “We need to give MHC-II and CD4 T cells greater respect when considering the players involved in shaping tumor phenotypes.”

The researchers found that MHC-II molecules typically present 12 to 16 amino acid peptides to CD4+ T cells. Marty said she hopes these new findings will inspire other researchers to integrate CD4 T cell response into their therapies. “Next, we are hoping to take the methods we have developed to study mutation development in early tumorigenesis and better understand the role of MHC variation in the response to therapies,” said Marty. 

Henry Chi Hang Fung, MD, FACP, FRCPE, vice chair in the Department of Hematology/Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania, said these findings point to a promising new avenue of treatment and may pave the way for looking at new molecular targets. However, they will need to be validated in other models. “This is an important study which may potentially lead to research directions and development of new therapy for cancer patients,” Fung told Cancer Network.