Abstract 4055: Immune checkpoint protein expression is up-regulated in tumor-bearing elderly mice

Abstract

Abstract Advancing age is a high risk factor of cancer occurrence. Also, cancer incidence rate of elderly people have been increased. Accordingly, treatment of elderly patients with cancer is one of the important worldwide issues. Aging is associated with dysregulated immune response, immunosenescence. In this study, we investigated that immunosenescence in tumor-bearing xenograft model was related to change of T cell subsets. MC38 colon carcinoma cells were injected s.c. in 2 months (young adolescent), 6 months (adult) and 18 months (elderly) old C57/BL6 mice. After 8 days, 10mg/kg oxaliplatin administered 1 time by intraperitoneal (IP) injection and tumor volume measured. We divided 4 groups in each age group (2, 6 and 18-months-old), vehicle (PBS)-treated normal mice, oxaliplatin-treated normal mice, tumor-bearing mice, and oxalpilatin-treated tumor-bearing mice, in 7 mice of each aged groups (2, 6 and 18-months-old). On day 30, mice were sacrificed. Splenocytes were stained with anti- CD4+, CD8+, CD44+, CD62L+, CD27+, CD28+, PD-1+ and TIM3+ to measure specific molecule expression of CD4+ and CD8+ T cells in the spleen. First, we analyzed the CD4+ and CD8+ T cell population whether T cell character was changed based on Aging. In elderly mice, total number of T cells was 52±10% decline compared to 2-month-old mice (p<0.0001). Both naïve CD4+ and CD8+ T cells decreased in elderly mice compared to young mice with reduction rate of 43.1±5%(P<0.0001) and 34.3±7%(P<0.0001), respectively. Then, we checked the expression of immune regulatory molecules such as PD-1 and TIM-3 on CD4+ and CD8+ T cells. In elderly mice, PD-1 level was up-regulated 1.8 times on CD4+ T cell and 0.9 times on CD8+ T cells. Next, we evaluated the T cell characters between normal and tumor bearing mice. In 2-month-old mice, tumor bearing affected to number of total T cell decline 52.98±3.8% compared to tumor absence mice (p<0.0001). As, the number of T cells was already decreased in normal mice sufficiently in 18-month-old group. The number of T cells was not different between tumor presence and absence in 18-month-old mice. Finally, we checked the change of T cell characters according to chemotherapeutic agent oxaliplatin treatment. Tumor volumes of 2-month-old mice were more decreased than 18-month-old when oxaliplatin was treated (41.8±15.2% reduction versus 16.6±21.9%). In oxaliplatin-treated, tumor-bearing 18-months-old mice, total T cell number was decreased more than 18-months-old tumor-bearing mice without treatment (45±32%, P = 0.025). Our results suggest that immunosenescnece have an effect to increase of immune checkpoint protein, such as PD-1, TIM-3. Therefore, novel treatment with immune checkpoint inhibitors is suggested as new therapeutic approaches in elderly patients. Citation Format: So Jung Lim, Jeong Min Kim, Won Suk Lee, Woo Sun Kwon, Tae Soo Kim, Kyu Hyun Park, Hyen Cheol Chung, Sun Young Rha. Immune checkpoint protein expression is up-regulated in tumor-bearing elderly mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4055. doi:10.1158/1538-7445.AM2015-4055