Minimally invasive colorectal resection: Association with elevated levels of plasma TIM-3 post surgery and effect on immune tolerance and the growth of residual metastases.

Abstract

219 Background: TIM-3 (T cell immunoglobulin and mucin domain-3) is a type I transmembrane glycoprotein expressed on CD4+ T helper 1 (Th1) and CD8+ T cytotoxic 1 (Tc1) T cells and endothelial cells. TIM-3, after binding to its ligand, Galectin-9, inhibits anti-tumor immune function. Co-expression of TIM-3 and PD-1 together is associated with enhanced dysfunctionality of tumor toxic CD8+ T cells. The combination of TIM-3 blockade with anti-PD-1 /PDL1 intervening therapy may enhance response. Tim-3 over expression has been associated with oncogenic activity in colorectal cancer(CRC). Persistently elevated plasma PDL1 levels after CRC resection have been reported. This study’s purpose was to measure plasma TIM3 levels before and during the first month after minimally invasive colorectal resection (MICR) for CRC. Methods: CRC patients (pts) in an IRB approved data/plasma bank who underwent MICR for whom plasma samples were available were studied. Clinical/pathologic data were reviewed. Blood samples were collected preoperatively (PreOp) and at 6 post-operative (Postop) time points (POD 1, 3, 7-13, 14-20, 21-27, 28-41) and processed. TIM3 levels were analyzed in duplicate using ELISA. Wilcoxon paired t-test was used for analysis. Results: A total of 96 CRC pts who had MICR met the study criteria (colon 72%; rectal 28%; mean age 64.8± 13.3). Compared to the mean PreOp plasma TIM3 levels (2619 ± 1410,n = 96;pg/ml ), significantly higher levels (p < 0.001)were noted on (POD)1(2823±1504,n = 95), POD3 (3469±1755,n = 89), POD7-13 (4317±1957,n = 79),POD14-20 (4779±3111,n = 26), POD 21-27(4553± 1846,n = 18) and on POD 28-41 (3621±1859,n = 21). Conclusions: Plasma TIM3 levels were significantly elevated over baseline for 1 month after MICR (% change range, 8-70; peak value weeks 2-4). The acute inflammatory response might account for the early increases but late elevations are more likely associated with wound healing/tissue remodeling. Elevated plasma TIM-3 levels may exhaust tumor infiltrating T-cells which may facilitate the growth of residual tumor. Further investigation is warranted.