New Study Disrupts a Long-Held Paradigm for Tumor Resistance to Immunotherapy

A study published today in Nature Cancer describes how tumors previously thought to be unresponsive to immunotherapy are responsive through a novel mechanism

The paper was authored by Duke MD/PhD student Emily Lerner, and co-author Peter Fecci, MD, PhD, Duke professor of neurosurgery.

Anti-tumor immunotherapies such as immune checkpoint blockade have revolutionized cancer treatment. Unfortunately, many solid tumors, including glioblastoma (GBM), have thus far failed to respond. Researchers are therefore investigating the mechanisms underlying tumor resistance to immunotherapy. 

One such proposed mechanism is tumor mutations leading to decreased or absent major histocompatibility complex I (MHC-I) expression. MHC-I proteins are normally found on the surface of all nucleated cells. MHC-I complexes present antigens to CD8 T cells, the main effector cells of the adaptive anti-tumor immune response. Cells that do not express MHC-I are therefore thought to be invisible to CD8 T cells. Downregulation of MHC-I by tumor cells has been suggested as a major mechanism of tumor resistance to CD8 T cell killing, and by extension, CD8 T cell-dependent immune checkpoint blockade therapy.  

“In this study, we found that CD8+ T cells can still kill tumor cells that are entirely devoid of MHC-I expression, a function previously thought to be restricted to the innate immune system,” said Lerner.  “We show that CD8 T cells can recognize tumor cells via the NKG2D receptor. This receptor binds to cell surface proteins that are upregulated in the setting of cellular stress and are highly expressed in tumor cells.”  

These findings bridge the gap between the adaptive and innate immune response in cancer and challenge the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape.  

Complete author list: Emily C. Lerner, Karolina I. Woroniecka, Vincent M. D’Anniballe, Daniel S. Wilkinson, Aditya A. Mohan, Selena J. Lorrey, Jessica Waibl-Polania, Lucas P. Wachsmuth, Alexandra M. Miggelbrink, Joshua D. Jackson, Xiuyu Cui,  Jude A. Raj, William H. Tomaszewski, Sarah L. Cook, John H. Sampson, Anoop P. Patel, Mustafa Khasraw, Michael D. Gunn, Peter E. Fecci.