Calcineurin-dependent effects of T cells in intestinal tumor development
Final Report Abstract
Colorectal cancer (CRC) is the fourth most common form of cancer worldwide and typically arises from sporadic somatic mutations in intestinal epithelial cells (IECs). Current data from our and other research groups show a significant contribution of the intestinal microbiota to CRC development and progression. The phosphatase calcineurin is expressed by mammalian cells in many different cell types and plays a central role in tissue homeostasis and immunity. This occurs, among other pathways, through dephosphorylation, nuclear translocation and activation of transcription factors of the nuclear factor of activated T-cells (NFAT) family, which is crucial for the function of innate and adaptive immune cells, as it is linked to the expression of cytokines such as IL-2, IL-4, IL-13 and IFN-γ. Therefore, pharmacologic inhibition of calcineurin quickly became a foundation in the treatment of chronic immune-mediated diseases and in the context of allogeneic transplantation. However, systemic inhibition of calcineurin is associated with an increase in various cancers, including colorectal cancer. Studies by our own research group had previously highlighted tumorprotective effects of calcineurin deletion in myeloid and epithelial cells. In this project, we therefore investigated whether tumor-promoting effects of systemic calcineurin inhibition are based on the blockade of calcineurin-dependent protective effects in T cells. To this end, we generated mice with T cell-specific calcineurin deletion. We demonstrate that these mice exhibited an increased number and accelerated growth of tumors in the ApcMin/+ model of spontaneous intestinal tumor development. This was due to reduced activation and proliferation of calcineurin-deficient CD8+ cytotoxic T-cells. In mechanistic studies, we showed that calcineurin regulates early steps of T-cell activation in an NFAT-independent manner by dephosphorylation of proteins within the T-cell receptor signaling cascade. This contributes to activation-induced changes in T-cell metabolism which are necessary for nucleotide synthesis and T-cell proliferation. Our results provide new insights into the pathways of metabolic control of antitumor immunity and reveal cell-specific roles of calcineurin in this process. These data also provide a mechanistic explanation for the observation of increased tumor incidence under systemic calcineurin blockade.
