Plasticity of Kupffer Cells in Regulating T Cell Surveillance and Immunotherapy Efficacy in PDAC

Abstract public domain (NIH RePORTER)

Project Summary Pancreatic ductal adenocarcinoma (PDAC) is predicted to emerge as the second leading cause of cancer-related deaths by 2030. This poor prognosis has largely been attributed to patients presenting with metastatic disease at the time of diagnosis and a profound resistance to standard treatment modalities. Current frontline therapies modestly extend survival for metastatic patients, thereby creating a high unmet need for new treatment paradigms. PDAC commonly metastasizes to the liver. However, the liver maintains a tolerogenic immune microenvironment to dampen excess activation of the immune system from the constant exposure to antigens and/or toxin from the intestines. Tissue-resident Kupffer cells (KCs) play a central role in regulating liver tolerance by suppressing T cell function during homeostasis – an effect which is detrimental during tumorigenesis. Previous work from our lab demonstrated that the pathogen associated molecule, β-glucan, can bind to Dectin-1 receptor on KCs and reprogram KCs to activate T cell-mediated cytotoxic immunity. KC reprogramming elicited robust anti-metastatic activity in PDAC and sensitized patients with metastatic disease to immune checkpoint blockade therapy. Importantly, KC and T cell interaction was indispensable in driving anti-metastatic activity of β-glucan. However, the precise mechanisms supporting β-glucan-driven KC activation of T cells are incompletely understood. Furthermore, preliminary data from our lab demonstrated that the anti-tumorigenic activity of β-glucan is lost during liver inflammation, indicating that KC function is dependent on signaling from the liver microenvironment. Therefore, the current K00 proposal will investigate the molecular interactions between KCT cells which lead to activation to T cell cytotoxic immunity and determine factors which govern KC phenotype during myeloid immunotherapy. β-glucan treatment upregulated MHC-I genes in KC and increased physical interaction between KC-T cells. Therefore, in Aim 1, I will investigate whether KCs engulf tumor cells to cross-present tumor antigens to T cells through MHC-I molecules. Additionally, I will test whether addition of myeloid receptor agonist CD40 to β-glucan works synergistically to invoke anti-tumor activity in PDAC. In Aim 2, I will determine whether liver inflammation impairs antigen presentation ability of KCs and reprograms KCs to suppress T cell function, thereby mediating myeloid therapy resistance. I will assess hepatocyte-derived extrinsic factors responsible for KC phenotype during liver inflammation. Together, this proposal will advance the current knowledge on KC biology, its role in regulating T cell immunosurveillance and the determinants which govern KC immunostimulatory or immunosuppressive phenotype during myeloid therapy in PDAC.

Public health relevance public domain (NIH RePORTER)

The liver microenvironment is rich in immunosuppressive myeloid cells like Kupffer cells which contribute to therapy resistance in pancreatic ductal adenocarcinoma (PDAC) patients with liver metastasis. This proposal will seek to reprogram Kupffer cells through myeloid-receptor activating immunotherapy to create productive T cell immunosurveillance and identify determinants regulating Kupffer cell function. Therefore, completion of this project will enable the identification of therapeutic strategies to overcome immune-evasion and resistance in PDAC liver metastasis.