Abstract 1690: JAK2 downmodulation leads to interferon gamma deficient response and resistance to immunotherapy in breast cancer
Authors: Lahuerta Enrique Javier Arenas , Martínez-Sabadell Alex , Ruiz Irene Rius , Alonso Macarena Román , Escorihuela Marta , Luque Antonio , Fajardo Carlos A. , Gros Alena , Klein Christian , Arribas Joaquín 
Published: July 2021

Abstract
Introduction: Elimination of cancer cells by effector immune cells represents the culmination of a complex cascade of events, and disruption of any of those events may result in resistance. T cell-engaging therapies, such as T cell bispecific antibodies (TCBs) or chimeric antigen receptors (CARs), are raising extraordinary expectations as future treatments for virtually all cancers. Encouraging these expectations, TCBs and CARs have been recently approved to treat some hematologic malignancies. In contrast, TCBs and CARs against solid tumors tested to date, have failed to show clinical efficacy. This failure prompted intense research and the subsequent identification of mechanisms of primary and acquired resistance. Different strategies are being implemented to overcome these mechanisms of resistance. All these mechanisms impinge on the ability of T cells to reach cancer cells and/or on the inhibition of T cells. However, little is known about putative intrinsic mechanisms of resistance of cancer cells. That is, mechanisms deployed by tumor cells to resist killing by fully active and correctly engaged T cells. In this study, we attempted to identify novel intrinsic mechanisms of resistance.
Methods: We have used TCBs and CARs targeting the cell surface receptor HER2 to identify a widespread mechanism of resistance to redirected T cells, using HER2-driven cell lines and Patient-Derived Xenografts (PDX).
Results: We have generated a model of intrinsic resistance to a TCB targeting HER2 by treating during 6 months co-cultures of PBMCs and parental BT474 cells. These resistant cells, named as BT-R, are also resistant to a HER2-CAR, in vitro and in vivo. Using this model, we identified by RNA-seq, a downmodulation of the IFN-gamma signaling pathway. Interestingly, using gain and loss of function approaches, we demonstrated that JAK2 loss is the cause of IFN-gamma deficient response, and as a consequence, resistance to HER2-TCB and CAR-HER2.
Conclusion: We have identified that the kinase JAK2, which transduces the signal initiated by interferon-gamma, is the component preferably disrupted to acquired resistance in all resistant models developed in vitro and in vivo. These results unveil a novel mechanism of resistance to T-cell based therapies, and imply the potential use of JAK2 and IFN-gamma response as a surrogate biomarker of response to immunotherapies. In addition, they open the avenue for the screening for therapies that can overcome deficient interferon-gamma response or restore JAK2 levels, which are promising potential candidates to increase the benefits of immunotherapies.
Citation Format: Enrique Javier Arenas Lahuerta, Alex Martínez-Sabadell, Irene Rius Ruiz, Macarena Román Alonso, Marta Escorihuela, Antonio Luque, Carlos A. Fajardo, Alena Gros, Christian Klein, Joaquín Arribas. JAK2 downmodulation leads to interferon gamma deficient response and resistance to immunotherapy in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1690.