IREα-XBP1s activation in leukocytes is associated with the level of exposure to paclitaxel in CIPN patients

Abstract

Chemotherapy induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy drugs; such as paclitaxel. Our laboratory is investigating the role of IRE1α-XBP1s arm of the endoplasmic reticulum stress response in immune cells under CIPN conditions. We have found that IRE1α-XBP1s in monocytes determines the development of CIPN induced by paclitaxel, and that its pharmacological inhibition prevents pain related behaviors in paclitaxel CIPN animals. However, we do not know whether IREα-XBP1s is altered in immune cells in human cancer patients experiencing CIPN. We would like to test this in patients with breast or cervical cancer treated with paclitaxel through the following aim, determine the levels of XBP1s mRNA (qPCR) and protein (immunohistochemistry and confocal microscopy) in peripheral leukocytes from patients exposed to paclitaxel at early (4-8 cycles) and later stages of treatment (8-16 cycles). We observed that the levels of XBP1s mRNA were significantly increased in peripheral blood mononuclear cells from CIPN patients that received 8-16 cycles when compared to their levels at early stages of treatment (4-8 cycles). Similarly, when we followed a patient receiving four cycles of paclitaxel, we observed an increase in XBP1s mRNA as paclitaxel exposure progressed. We also observed similar findings in skin biopsies of patients with paclitaxel treatment (early and late exposure). Using IHC we observed an increase in XBP1s protein in parallel to an increase in IBA1 expressing cells (macrophages), and an increase in IBA1 cells co-expressing XBP1s in samples obtained after 8-16 cycles of paclitaxel when compared to earlier exposure (4-8 cycles). We conclude that paclitaxel exposure is associated with the activation of the IRE1α-XBP1s in immune cells in patients with CIPN. Our data provides a translational foundation that support the value of this molecular pathway as a potential target and/or biomarker for disease progression. Department of Anesthesiology-Wake Forest School of Medicine Funds, Comprehensive Cancer Center-Wake Forest School of Medicine Funds, NIDA R21CA248106, National Center for Advancing Translational Sciences (NCATS)-NIH through Grant Award Number UL1TR001420. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.