Cancer Vaccine Prevents Tumor Formation and Metastasis by a Dual Immune Cell Attack

Major histocompatibility complex (MHC) class I chain-related protein A (MICA) and MHC class I chain-related protein B (MICB) proteins are found on the surface of cancer cells but are expressed at low or undetectable levels by healthy cells. MICA/B proteins are normally recognized by immune cells like T cells and natural killer (NK) cells, which when activated produce cytokines and promote cytotoxicity. However, some cancer cells shed these MICA and B proteins to escape immune detection.  

A Dana-Farber team led Kai Wucherpfennig, MD, PhD, and Glenn Dranoff, MD, along with David Mooney, PhD of the Wyss Institute, have developed a cancer vaccine that prevents MICA/B protein shedding, essentially locking them in place to be recognized by the immune system and killed.  

The vaccine induces a coordinated attack of cancer cells by diverse types of immune cells, including T cells and NK cells. Cellular stress such as oncogenic transformation results in elevated levels of membrane-bound MICA/B stress proteins. The increased levels of MICA/B on the cell surface signals to the immune system that the cell should be removed. Binding of the T cells and NK cells to MICA/B stimulates the anti-cancer responses to eliminate the transformed cell. To evade the immune system, cancer cells shed the MICA/B proteins from the cell surface resulting in fewer antigens for immune cells to target.  

The vaccine strategy developed by the team relies on antibodies that target the α3 domain on the MICA/B proteins, the site where the proteins are cleaved by the tumor cells. Antibodies made by the body following administration of the MICA/B cancer vaccine block the cleavage of MICA/B, thereby preventing their shedding and increasing the density of the MICA/B proteins on the tumor cell surface. Retaining the proteins on the cell surface not only allows for NK cells and T cells to directly recognize and eliminate the cancer cells, but also  results in recruitment of dendritic cells to the tumor expanding the anti-cancer activity of the response to cancer cells that have lost expression of MHC Class I, another common immune evasion mechanism exploited by cancer cells.    

An alternative approach to prevent shedding of MICA/B from the cancer cell surface using a monoclonal antibody has demonstrated early signs of efficacy in Phase I clinical trials (NCT05117476). However, the Dana-Farber scientists have found that the vaccine approach stimulates additional immune mechanisms, including increasing immune infiltration into the tumors that is not observed with the monoclonal antibody approach. Together, these data help to de-risk the approach of blocking MICA/B shedding and suggest that the vaccine approach has advantages over the competition.