Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation

Enrique J Arenas,Alena Gros,Antonio Luque,Carlos Alberto Fajardo,Christian Klein,Alex Martínez-Sabadell,Joaquín Arribas,Marta Escorihuela,Macarena Román Alonso,Irene Rius Ruiz

doi:10.1038/s41467-021-21445-4

Abstract

Immunotherapy has raised high expectations in the treatment of virtually every cancer. Many current efforts are focused on ensuring the efficient delivery of active cytotoxic cells to tumors. It is assumed that, once these active cytotoxic cells are correctly engaged to cancer cells, they will unfailingly eliminate the latter, provided that inhibitory factors are in check. T cell bispecific antibodies (TCBs) and chimeric antigen receptors (CARs) offer an opportunity to test this assumption. Using TCB and CARs directed against HER2, here we show that disruption of interferon-gamma signaling confers resistance to killing by active T lymphocytes. The kinase JAK2, which transduces the signal initiated by interferon-gamma, is a component repeatedly disrupted in several independently generated resistant models. Our results unveil a seemingly widespread strategy used by cancer cells to resist clearance by redirected lymphocytes. In addition, they open the possibility that long-term inhibition of interferon-gamma signaling may impair the elimination phase of immunoediting and, thus, promote tumor progression.

Highlights

Immunotherapy has raised high expectations in the treatment of virtually every cancer
Addition of picomolar concentrations of this HER2-T cell bispecific antibodies (TCBs) to cocultures of peripheral blood mononuclear cells (PBMCs) and the HER2overexpressing BT474 cells led to the killing of the latter (Supplementary Fig. 1b)
It should be noted that the IC50 of HER2-TCB for a given ratio PBMC:BT474 varied depending on the donor of PBMCs

Summary

Introduction

Immunotherapy has raised high expectations in the treatment of virtually every cancer. Our results unveil a seemingly widespread strategy used by cancer cells to resist clearance by redirected lymphocytes They open the possibility that long-term inhibition of interferon-gamma signaling may impair the elimination phase of immunoediting and, promote tumor progression. Using HER2-driven cell lines and patient derived xenografts (PDXs), and a TCB and CAR targeting HER2, here we describe experiments that unveil a mechanism of resistance to redirected T cells. This mechanism should be taken into consideration when designing strategies to increase the efficacy of cancer immunotherapies

Methods

Results

Conclusion