Exploring engineered HLA-I chaperones for enhancing the immunogenicity of cold tumors.

Abstract

Abstract Immune surveillance relies upon efficient production of peptide loaded HLA class I molecules (pHLA-I), a process mediated by the antigen processing and presentation (APP) pathway. Accordingly, dysregulation of the APP pathway is a common immune evasion mechanism in cancers. This is especially true for “cold tumors”, a class of cancers with low immunogenicity, typically caused by global downregulation of pHLA-I and/or low mutational burden, resulting in immune escape and overall worse prognosis. We aimed to develop a method for restoring immunological recognition of this class of tumors by leveraging endogenous mediators of the APP pathway. We modified two important HLA-I chaperones, tapasin and TAPBPR, which have essential functions in stabilizing HLA-I molecules and in refining the repertoire of presented antigens. We have engineered variants of these chaperones, including HLA allotype-agnostic variants, which travel along the secretory pathway together with HLA molecules, enabling them to exert their chaperoning function in non-native subcellular compartments, including at the cell surface. We show that these Chaperone Fusion Proteins (CFPs) can increase HLA-A2 expression in multiple cell lines, including in a bona fide cold tumor cell line. Moreover, CFP expression resulted in enhanced T cell recognition and killing of target tumor cells. These data suggest that CFPs may be developed into a platform for enhancing the immunogenicity of cold tumors.