Combining Therapies to Fight Cancer

Immunotherapies have revolutionized the care of many cancers. Leading the way are drugs known as checkpoint inhibitors, which block a protein called PD-L1 that many tumors are coated in. When PD-L1 on the surface of a cancer cell sees its partner, PD1, on T cells, these T cells are tricked into letting the cancer cell live. To counteract this trick, checkpoint inhibitor drugs block the functions of either PD-L1 on tumor cells or PD1 on T cells.

Unfortunately, checkpoint inhibitors don’t work all the time. In a study published today in Cancer Immunology Research, scientists show in mouse models of B-cell lymphoma that adding another drug called a histone deacetylase (HDAC) inhibitor sensitized cancers to anti-PD1 therapy.

The reason this works involves another set of proteins called the major histocompatibility complex (MHC), which presents cellular proteins on the cell’s surface for inspection by T cells. When T cells recognize a dangerous antigen on the MHC, they attack that cell—unless the T cell is deactivated by the PD1/PD-L1 interaction. If a cancer cell has no MHC proteins, it doesn’t matter if immunotherapy blocks the PD1/PD-L1 interaction; without MHC, the cancer cell presents no antigens and so the immune system sees no danger.

“T cells recognize antigens in the context of MHC. Without MHC, you can’t present an antigen,” says Jing Wang of the University of Colorado. “And about 60% of diffuse large B cell lymphomas downregulate MHC.”

However, it appears that the class of drugs known as HDAC inhibitors upregulate MHC.  “We treated our mouse model of B-cell lymphoma with this HDAC inhibitor,” Wang says. “The inhibitor alone had some effect, but when we combined it with anti-PD1, it worked a lot better. Dual inhibition—both HDAC and PD1—achieved a better effect.”

The study helps explain why previous HDAC inhibitors have struggled. HDAC inhibitors may upregulate MHC proteins, but the current study shows that HDAC inhibitors may also upregulate PD-L1. This makes it easier for cancer cells to deactivate T cells. But if an HDAC inhibitor is administered alongside a checkpoint inhibitor that blocks the PD1/PD-L1 interaction, we reap the both of best worlds: the HDAC inhibitor will upregulate MHC while the checkpoint inhibitor prevents cancer cells from deactivating T cells.