Solid tumors generate a suppressive environment that imposes an overwhelming burden on the immune system. Nutrient depletion, waste product accumulation, hypoxia, and pH acidification severely compromise the capacity of effector immune cells such as T and natural killer (NK) cells to destroy cancer cells. However, the specific molecular mechanisms driving immune suppression, as well as the capacity of immune cells to adapt to the suppressive environment, are not completely understood. Thus, here, we used an in vitro microfluidic tumor-on-a-chip platform to evaluate how NK cells respond to the tumor-induced suppressive environment. The results demonstrated that the suppressive environment created by the tumor gradually eroded NK cell cytotoxic capacity, leading to compromised NK cell surveillance and tumor tolerance. Further, NK cell exhaustion persisted for an extended period of time after removing NK cells from the microfluidic platform. Last, the addition of checkpoint inhibitors and immunomodulatory agents alleviated NK cell exhaustion.
Objective
To determine the role of the aryl hydrocarbon receptor (AHR) in colitis-associated colorectal tumorigenesis.
Summary Background Data
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women in United States. Chronic intestinal inflammation increases the risk for the development of CRC. We questioned the involvement of AHR, a transcriptional regulator for intestinal innate immunity and inflammation, in the colitis-associated tumorigenesis.
Methods
We used a mouse model for chemically-induced colorectal tumorigenesis by treatment of azoxymethane (AOM) and sodium dextran sulfate (DSS). We examined the role of AHR using Ahr-deletion mouse model and I3C treatment. Tumor incidence, number and location were visually counted. Tumor multiplicities were evaluated and compared using GraphPad Prism software (version 6, LaJolla, CA).
Results
In Ahr null mice, the tumor incidence was 32% increased and the mean tumor number was approximately 3 time increased compared to WT mice (7 v 2.4, P<0.05). The tumor number was 92% decreased by treatment of I3C in WT mice, while the chemopreventive effect of I3C was not observed in Ahr null mice (P<0.05).
Conclusions
We found that the AHR may play a protective role in colitis-associated colorectal tumorigenesis. This work supports the application of AHR agonists such as I3C as a chemopreventive therapy for CRC in human patient.
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