S100A9-Regulated Functions of Myeloid-Derived Suppressor Cells in Small Cell Lung Cancer
Abstract
Small cell lung cancer (SCLC) is an urgent priority among Veterans as evident by not only higher incidence rate, but the survival is lower than in civilian populations. Our goal is to understand the molecular mechanisms of initiation and progression to clinically significant SCLC and identify innovative strategies for prevention and treatment of early and/or localized lung cancer. Among lung cancer, SCLC is a highly aggressive metastatic disease. SCLC patients have limited spectrum of therapeutic options available to them. Furthermore, SCLC patients develop drug resistance to these therapies. Therefore, there is an utmost need to develop novel therapies against SCLC. We are planning to understand mechanisms that suppress immune responses. In this context, we are analyzing the role of S100A9 on immune cell responses against SCLC. We have observed that S100A9, a small molecular weight inflammatory protein, expression correlates with poor overall survival rate in SCLC patients. We hypothesize that S100A9 enhances SCLC progression, drug resistance, and metastasis by suppressing anti-tumor immunity. We further hypothesize that S100A9 enhances immune-suppressive microenvironment through recruitment of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in SCLC. In this proposal, we will determine if S100A9 enhances recruitment and activation of MDSCs to SCLC tumors using different SCLC mouse model including genetically engineered SCLC mouse model. We will further determine if S100A9 inhibitor inhibits SCLC growth and metastasis using preclinical mouse model. In addition, we will determine the effect of S100A9 inhibitor on SCLC drug resistance. Next, we will analyze if S100A9 inhibitor treatment decreases MDSCs and TAMs activity and thereby enhances immunity against tumors. This study will provide important and novel insights about the role of S100A9 in suppressing immune responses against SCLC. It might also revolutionize the current understanding of drug resistance in SCLC, based on role of S100A9 in enhancing functions of MDSCs and TAMs. Finally, this study will evaluate the potential impact of S100A9 inhibitor on SCLC growth and drug resistance using preclinical SCLC mouse models including genetically engineered SCLC mouse models that develop spontaneous tumors that are similar to human tumors.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710227
Entities
People
- Ramesh K. Ganju
Organizations
- Ohio State University
- United States Army