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SYSTEMIC AND LOCAL MYELOID INFLAMMATION IS ASSOCIATED WITH POOR OUTCOME FOLLOWING SYNCHRONOUS RESECTION OF PRIMARY COLORECTAL CANCER (CRC) AND LIVER METASTASES
Colin W. Steele*1,3, Campbell S. Roxburgh1,2, Joanne Edwards2, Donald C. McMillan1, Paul Horgan1, Owen Sansom3,2
1University Department of Surgery, Glasgow Royal Infirmary, Glasgow G40SF, University of Glasgow, South Lanarkshire, United Kingdom; 2Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom; 3Beatson Institute for Cancer Research, Glasgow, United Kingdom
BACKGROUND
EFFECTOR T CELL INFILTRATION OF PRIMARY AND METASTATIC CRC, MEASURED BY IMMUNOSCORE, AND KLINTRUP-MAKINEN SCORING (KM), IS ASSOCIATED WITH LONGER PATIENT SURVIVAL. CONTRASTINGLY, MYELOID CELL-INDUCED INFLAMMATION, MEASURED SYSTEMICALLY BY NEUTROPHIL: LYMPHOCYTE RATIO (NLR) AND BY QUANTIFYING AND CHARACTERISING MYELOID CELLS IN TUMORS, IS ASSOCIATED WITH POOR OUTCOME FOLLOWING RESECTION OF PRIMARY CRC AND IS BELIEVED TO DAMPEN EFFECTOR T CELL RESPONSES. MYELOID TARGETING DRUGS ARE AVAILABLE FOR TRIAL IN METASTATIC DISEASE WHICH HAS SO FAR PROVEN RESISTANT TO T CELL DIRECTED IMMUNOTHERAPIES.
AIM
ESTABLISH THE IMPORTANCE OF MYELOID CELL-MEDIATED SYSTEMIC AND TUMORAL INFLAMMATION ON OUTCOME FOLLOWING SYNCHRONOUS RESECTION OF PRIMARY CRC AND LIVER METASTASES.
METHODS
WE EXAMINED SYSTEMIC AND LOCAL MYELOID CELL MEDIATED INFLAMMATION IN 46 PATIENTS WHO HAD SYNCHRONOUS RESECTION OF PRIMARY CRC AND LIVER METASTASES AT A SINGLE INSTITUTION, BETWEEN 1998 AND 2009. VIA NLR, KM SCORING, AND IMMUNOHISTOCHEMICAL STAINING FOR MACROPHAGES, AND CD8+ T CELLS, WE EXAMINED SYSTEMIC AND INTRATUMORAL IMMUNE CELL RELATIONSHIPS AND THEIR INFLUENCE ON SURVIVAL FOLLOWING SURGERY. WE PERFORMED BIVARIATE CORRELATION ANALYSIS USING PEARSON'S STATISTIC AND KAPLAN MEIER ANALYSIS OF SURVIVAL.
RESULTS
WE CONFIRMED HIGH PRIMARY CRC KM PREDICTED LONGER SURVIVAL FOLLOWING SYNCHRONOUS RESECTION OF PRIMARY CRC AND METASTASES (P<0.001). HOWEVER, THERE WAS NO SIGNIFICANT INFLUENCE OF KM OR CD8+ T CELL DENSITY WITHIN METASTASES ON OUTCOME. ELEVATED NLR WAS ASSOCIATED WITH POOR SURVIVAL FOLLOWING SYNCHRONOUS SURGERY FOR CRC AND LIVER METASTASES (P<0.001), WAS STRONGLY CORRELATED WITH PRIMARY CRC MACROPHAGE DENSITY (P=0.046), AND INVERSELY CORRELATED WITH KM (P=0.032). HIGH MACROPHAGE DENSITY WITHIN PRIMARY CRC WAS ASSOCIATED WITH POOR OUTCOME (P=0.09). THOUGH THE QUANTITY OF MACROPHAGES WAS GREATER IN THE METASTATIC THAN PRIMARY SITE (P<0.001),THEIR PRESENCE IN METASTASES HAD NO INFLUENCE ON SURVIVAL.
DISCUSSION
MYELOID CELL-MEDIATED SYSTEMIC AND LOCAL INFLAMMATION IS ASSOCIATED WITH POOR OUTCOME FOLLOWING SYNCHRONOUS RESECTION OF PRIMARY CRC AND LIVER METASTASES. THEREFORE, TARGETING MYELOID CELL POPULATIONS MAY BE A USEFUL STRATEGY IN METASTATIC CRC TO PROMOTE T CELL RESPONSES. ASSESSMENTS OF THE PRIMARY TUMOR NICHE CARRIED GREATER PROGNOSTIC INFORMATION THAN THE METASTATIC NICHE IN THESE PATIENTS SUGGESTING THE IMPORTANCE OF THE PRIMARY TUMOR MICROENVIRONMENT AND ASSOCIATED SYSTEMIC COMPONENT OF INFLAMMATION IN DRIVING METASTATIC PROGRESSION. MACROPHAGES OFTEN EXPRESS ANTI-TUMORAL FACTORS IN PRIMARY CRC. THESE DATA SUGGEST MACROPHAGES ADOPT TUMOR PROMOTING PHENOTYPES TO PERMIT METASTATIC PROGRESSION. FURTHER CHARACTERISATION OF MYELOID CELLS IN THE PRIMARY AND METASTATIC TUMOR MICROENVIRONMENT IS REQUIRED TO APPROPRIATELY TARGET SUBSETS OF PROTUMORIGENIC MYELOID CELLS IN FUTURE TRIALS.
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