Myeloid-derived suppressor cells (MDSCs) are now established as one of critical factors regulating immune responses in cancer. These cells are characterized by common myeloid origin, immature state and immune suppressive activity. Immature myeloid cells (IMC) with the same phenotype as MDSCs are continually generated in the bone marrow of healthy individuals and differentiate into mature myeloid cells without causing detectable immunosuppression. However, in cancer, normal myeloid cell differentiation is diverted from its intrinsic pathway of terminal differentiation of mature macrophages (MF), dendritic cells (DCs), or polymorphonuclear neutrophils (PMN) and instead favors differentiation of pathological MDSCs. The frequency of MDSC correlates with a poor prognosis and progression in cancer patients. A direct relationship between tumor burden and MDSC frequency has been demonstrated in several mouse tumor models and clinical studies, as well as, an inverse correlation between MDSC and T-cell frequency in the peripheral blood. Despite wealth of information regarding MDSC biology, what causes IMC to acquire immune suppressive activity remains largely unclear. Lack of understanding of the exact mechanisms responsible to conversion of IMC to MDSC during tumor progression limits not only our view of myeloid cell biology but also attempts in regulation of these cells with therapeutic purposes. Suppressive features of MDSC would present a unique opportunity to use these cells for cell therapy of graft versus host disease (GVHD) in bone marrow transplantation as well as many autoimmune conditions. However, generation of human and mouse MDSC in vitro without the use of tumor conditioned medium remains elusive. This hampers the attempts to bring this approach to clinical trials. We recently have found that human and mouse MDSC, in contrast to control monocytes and PMN, displayed signs of endoplasmic reticulum (ER) stress. We propose that ER stress may play a major role in regulation of immune suppression function of these cells. In this application we plan to investigate the mechanisms and functional consequences of ER stress in MDSC. We will explore the possibility of using this novel observations for generation of human and mouse MDSC in vitro, for potential clinical use. This application include three specific aims:
Specific Aim 1. To evaluate of ER stress response in MDSC during tumor progression Specific Aim 2. To determine the mechanisms of ER stress effect on MDSC function.
Specific Aim 3. To identify the mechanisms of ER stress induction in MDSC and their possible use for therapeutic purposes.
This proposal addresses in preclinical setting important clinical problem - tumor escape from immune therapy. We will investigate the basic mechanism of this phenomenon associated with endoplasmic reticulum stress response. We will test this novel mechanism and its correction in relevant mouse models of melanoma and pancreatic cancer and determine its clinical relevance using samples from patients with lung and head and neck cancer.
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