HLA-E Inhibition Sensitizes Cancers to Immunotherapy

Project Overview

• New cancer immunotherapies are needed to overcome acquired resistance to existing treatments and increase the number of responding patients.
• Dana-Farber scientists have discovered the inhibition of HLA-E improves immunotherapy response in some cancers.

Technology

Identifying tumor-intrinsic and tumor microenvironment mechanisms that enhance response to immunotherapy is the focus of intense preclinical and clinical investigations. However, studies tend to use either in vitro models or test limited sets of candidate pathways in vivo. These approaches have precluded the discovery of immune resistance mechanisms in the multicellular ecosystem of the tumor microenvironment. A team from Dana-Farber overcame these limitations and identified immune evasion mechanisms using genome-scale in vivo screens across multiple tumors with distinct genetic drivers and tissues of origin. 

The scientists identified key immune evasion mechanisms common across cancer types. Specifically, they identified HLA-E, the non-classical major histocompatibility complex class I molecule and the ligand for the NKG2A/CD94 receptor, and demonstrated that inhibition of HLA-E enhances response to immune checkpoint blockade in models of pancreatic and renal cancers, and melanoma. 

Team Members: W. Nicholas Haining, BM, BCh, Robert Manguso, PhD

Applications

Inhibition of HLA-E enhanced the response to immunotherapy in all cancer types tested. HLA-E inhibition enhanced the response of anti-PD-1 antibodies and has the potential to synergize with additional immunotherapies.

Opportunities

Dana-Farber is looking for licensing opportunities for preclinical and clinical development of HLA-E targeting modalities.