Role of Macrophage-induced Inflammation in Mesothelioma

Abstract

Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 5f. WORK UNIT NUMBER REPORT DATE July 2012 REPORT TYPE PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERUniversity of California San Francisco, CA 94143-0962 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTMacrophages are a major inflammatory cell in malignant pleural mesothelioma and may help maintain tumor resistance to therapy. In this final year, we have completed the key tasks that confirm the importance of the macrophage in the inflammatory cell environment of mesothelioma. We have confirmed that it is possible to alter the polarization of macrophages to either an M1 (anti-tumor) or M2 (pro-tumor) phenotype and that a shift toward the Th1 phenotype or depletion of macrophages increases mesothelioma cell apoptosis and chemosensitivity. In our orthotopic murine mesothelioma model, the depletion of macrophages increases the mesothelioma response to chemotherapy. We have recently used a non-toxic CSF1 receptor inhibitor already in clinical trials to manipulate macrophages and shown that the tumors become more responsive to chemotherapy regimens used in patients with mesothelioma. At the end of our three year award, we have convincing evidence that manipulation of macrophages can alter the response of mesothelioma to standard therapy. Our major publications on these findings are in preparation and an RO1 application with a clinical trial included is planned for submission this fall. SUBJECT TERMSNone provided. I. INTRODUCTIONInflammation is an early and consistent feature of mesothelioma [1, 2], an incurable tumor with a high level of resistance to chemotherapy [3]. Within this inflammatory milieu, we have discovered that there is a large population of macrophages, in a higher percentage than we have found in other thoracic malignancies. The macrophage is perhaps the earliest cell recruited to the asbestos...