Abstract 4638: The p53 suppression on tumor cells may recruit macrophages and modulate their expression of the indoleamine 2, 3-dioxygenase
Authors: Nakamura Takafumi 
Published: July 2017

We had found that expression of indoleamine 2,3-dioxygenase (IDO) on cervical cancer cells increased as it progressed from carcinoma in situ (CIS) to microinvasive cancer, and that tumor-associated macrophages (TAM) recruited at the invasive front also expressed IDO in cervical cancer patients (Cancer Sci 98:874-881 2007). We previously produced homozygous αT3 transgenic mice carrying two copies of αA-SV40Tag transgene (αA denotes murine αA-crystallin promoter) in order to study DNA virus-induced carcinogenesis. The αT3 mice developed undifferentiated cancer of lens epithelium, which tumors showed multi-step carcinogenesis which was similar to cervical cancer (J Cancer Res Clin Oncol 135:1521-1532 2009). We found that homozygous αT3 mice carrying two copies of SV40Tag transgene progressed faster and died earlier than hemizygous αT3 mice carrying one copy of Tag transgene. In this study, in order to examine the relationship between p53 function and tumor progression, αT3 mice were mated with M1 mice expressing mutant p53 in lens cells (Proc. Natl. Acad. Sci. USA, 92:6142-6146, 1995) producing αT3M1 mice, and also were mated with p53-deficient mice to produce p53-deficient αT3 (αT3p53(-/-)) mice( Cancer Letters 179:165-173,2002, Oncology Report 12:253-258, 2004). At 20 weeks of age, the proportion of progression from CIS to invasive cancer was analyzed by H&E staining and the number of recruited TAM and IDO-expressing TAM were determined by immunohistochemical staining and FACS analysis. Pathologically, both αT3M1 and αT3p53(-/-) lens tumors significantly progressed to invasive cancer more than αT3 tumors. There were a few macrophages in wild-type lens, but more TAM were recruited in both αT3, αT3M1 and αT3p53(-/-) lens tumors. However, no significant difference of the number of IDO-expressing macrophages in peritoneal cavity was detected in each mice of wild-type, αT3, αT3M1 and αT3p53(-/-). It suggested that p53 suppression on tumor cells might modulate IDO-expression for macrophages. Moreover, we established the tumor cell lines from each αT3, αT3M1 and αT3p53(-/-) lens tumors. The peritoneal macrophages were analyzed for IDO-expression in 4 days after i.p. injection of these cells. Significantly, IDO-expressing macrophages in peritoneal cavity were more detected after i.p. injection of each αT3M1 and αT3p53(-/-) cells than i.p. injection of αT3 cells. And the co-culture of peritoneal macrophages with each αT3M1 and αT3p53(-/-) tumor cells also induced the IDO-expression of macrophages more than the co-culture with αT3 cells. These results suggested that the amount of p53 suppression on tumor cells would be related to the number of recruited TAM and their expression of IDO. The p53 suppression on tumor cells may recruit TAM and affect the macrophage function and, suppress an innate immunity possibly through the expression of IDO, which may enhance invasion and progression of tumors.

Citation Format: Takafumi Nakamura. The p53 suppression on tumor cells may recruit macrophages and modulate their expression of the indoleamine 2, 3-dioxygenase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4638. doi:10.1158/1538-7445.AM2017-4638