Research Projects

Tumor cells evade anti-tumor immune response through the activation of cell intrinsic pathways as well as modulating tumor microenvironment. Down regulation of MHC1 antigen presentation pathway constitutes a major immune evasive mechanism. Presentation of intracellular antigens loaded on MHC1 molecules is critical for CD8 T cell activation. At the transcriptional level MHC1 pathway is induced by IFNγ through its binding to IFNGR receptor resulting in expression of NLRC5, MHC1 pathway (HLA-A, B, C, TAP1, LMP2, LMP7) and PDL1. IFNγ has been shown to be toxic to tumor cells and tumor cells downregulate IFNGR receptor, which would ultimately affect the expression of MHC1 pathway and in turn lead to defective antigen presentation and immune evasion. However, analysis of MHC1 expression at the single cell level in PDAC samples did show at least some basal MHC1expression even though IFNGR receptor expression was severely compromised indicating an IFNγ independent pathway being operational (Yousuf et al, unpublished data). Earlier studies have indicated the role of NLRC5 as being transcriptional regulator of MHC1 pathway and constituted an important target for immune evasion (Yoshihama et al, 2017 PNAS). Our recent studies with neoadjuvantly treated PDAC patients showed that MHC1 expressing tumor regions were selectively targeted by reactivated immune response, indicating that in principle tumor cells are susceptible to immune mediated killing provided such cells express MHC1 pathway genes. However, due to dual nature of IFNγ signalling pathway affecting the expression of both MHC1 as well as PDL1 genes which could have again led to dysfunctional T cell state, we hypothesize that such MHC1 induction happens through some different pathway probably activating NLRC5 which inturn leads to MHC1 expression without affecting PDL1. One such possibility could be through cGAS-STING-IRF3 pathway possibly activated by nucleic acids released from surrounding necrotic cells upon treatment. Within this proposal we aim to establish that NLRC5 constitutes an important transcriptional regulator of MHC1 pathway in PDAC and there is a compensatory mechanism activated within Tumor microenvironment which induces NLRC5 expression in absence of IFNγ pathway. We further hypothesize that tumor cells downregulate NLRC5 expression hence evading CD8 T cell mediated immunity and sub section of patients with high NLRC5 expression have better prognosis owning to higher CD8 T cell infiltration within tumor nests. The experiments will be performed on Kras mutant cancer lines (PANC-1, MIA-PACA-2). Multiplex immunohistochemistry will be used for spatial analysis of TME using human PDAC samples (n=100) and orthotopic mice models will be used to establish the role of NLRC5 in tumor progression. The conclusions drawn from this project will extend our understanding of MHC1 regulation in PDAC and reliably present mechanisms employed by cancer cells to evade CD8 T cell mediated immunity.