Hepatitis C virus-cross-reactive TCR gene-modified T cells: A model for immunotherapy against diseases with genomic instability

Abstract

Abstract A major obstacle hindering the development of effective immunity against viral infections, their associated disease, and certain cancers is their genomic instability. Accumulation of mutations can alter processing/presentation of antigens recognized by antibodies and T cells leading to immune escape variants. A therapeutic agent that can combat rapidly mutating viral or cancer-associated antigens would be advantageous in providing effective immunity. We propose T cells harboring cross-reactive TCRs may offer a solution in these instances. Using hepatitis C virus (HCV), known for its genomic instability, as a model for mutant antigen recognition, we demonstrate cross-reactivity of TCRs against immunogenic and mutagenic NS3:1406-1415 and NS3:1073-1081 epitopes in TCR-gene-modified T cells. Our approach includes (1) functional studies demonstrating crossreactive profiles; (2) epidemiological data supporting the relevance of mutant epitope prevalence in infected individuals; (3) TCR-pMHC structural modeling to rationalize how TCR structural properties accommodate recognition of certain mutated epitopes and how they impact the requirement of CD8; lastly, we (4) provide preliminary clinical evidence of cross-reactive TCR benefit in that T cell clones isolated from HCV-infected patients who spontaneously resolved infection exhibited broader cross-reactivity compared to those of individuals with chronic infection. Together this approach serves as a model to address diseases with genomic instability and highlights potential benefit of cross-reactive TCRs. A better understanding of such TCRs’ promiscuous behavior may allow for exploitation of these properties to develop novel adoptive T cell-based therapies.