Interrogating mechanisms of tumor-specific T cell exhaustion and activity in pancreatic ductal adenocarcinoma

Progress developing immune-based treatments to treat the highly lethal pancreatic ductal adenocarcinoma (PDA) has lagged behind other cancer types. This may be due, in part, to a fibroinflammatory and immunosuppressive tumor microenvironment (TME). To investigate mechanisms of resistance, we developed a novel mouse model to track pancreatic-tumor specific T cells.  While expression of the bioluminescent molecule click beetle red (CB) by tumor epithelial cells permits longitudinal imaging of pancreatic tumor growth in vivo, CB also and unexpectedly generates an immunodominant CD8 T cell epitope (CB101-109:H-2Db) in C57Bl/6 mice. Orthotopic implantation of CB+ PDA cells into syngeneic immunocompetent mice results in the activation, expansion and intratumoral accumulation of CB-specific T cells, thereby modeling the large fraction of PDA cases that have a significant T cell infiltrate. We created a peptide:MHC tetramer to detect CB-specific T cells and demonstrate robust T cell infiltrate. Nonetheless, PDA  induces a state of intratumoral T cell exhaustion characterized by loss of effector functions such as IFN-γ, TNF-α and GzmB and acquisition of regulatory functions such as the production of IL-10. We show that myeloid cells infiltrating PDA produce IL-27, which drives IL-10 production by T cells. Unexpectedly, αCD40 agonist ameliorates intratumoral myeloid cell IL-27 expression and T cell exhaustion, whereas αPD-L1 treatment promotes expansion of splenic CB-specific CD8 T cells. Combination agonistic αCD40 + αPD-L1 resulted in tumor clearance in 63% of animals and generated robust T cell memory. This therapy required IFNγ signaling whereas abrogating TNFα signaling resulted in cures in 100% of treated animals. In sum, this novel PDA animal model provides a tractable and rigorous longitudinal analysis of tumor-specific CD8 T cells which can inform the development of more effective immunotherapy combinations for patient treatment.

Learning Objectives:

1. Identify potential mechanisms driving resistance to immune therapy in pancreatic cancer

2. Appreciate the value of interrogating antigen-specific T cells in the context of disease

3. Elucidate how the tumor microenvironment plays a role in driving T cell exhaustion in malignancy and how combination therapies can operate to interfere with T cell exhaustion