Abstract IA9: Immune surveillance and CD40 therapy of pancreatic cancer in mice and humans.

To understand T cell immune surveillance in pancreatic ductal adenocarcinoma (PDA), our laboratory has studied the KPC genetically engineered mouse model of this disease. Unexpectedly, we found that effector T cells are scarce in both preinvasive and invasive lesions, whereas immune suppressive cells, including tumor-associated macrophages, immature myeloid cells, and regulatory T cells, are prominent at even the earliest stages of neoplasia and persist through invasive cancer. These findings are consistent with the immune infiltrate observed in human PDA in which a marked macrophage and myeloid cell infiltration is associated with few effector T cells. Because suppressive cells of the immune system appear early during pancreatic tumorigenesis, we hypothesize that the absence of effector T cell immune surveillance in PDA may be more consistent with “immunological ignorance” than “immunoediting.” In this scenario, PDA cells may be particularly sensitive to T cell killing because of a lack of T cell selective pressure in vivo. To explore this hypothesis, we have evaluated a CD40 agonist antibody for its ability to reverse immune suppression and activate the immune system. In patients with metastatic pancreatic cancer, we found that a CD40 agonist antibody in combination with gemcitabine led to major tumor regressions in a fraction of patients. To understand the mechanism of this effect, we studied two murine models of PDA: (1) a transplant model in which PDA tumor cell lines derived from KPC mice are implanted into syngeneic littermates and (2) the spontaneous KPC model of PDA. We have found that PDA tumors implanted subcutaneously into non-KPC mice grow readily, but upon treatment with an agonist CD40 mAb and gemcitabine, established PDA tumors undergo complete regression associated with a robust T cell infiltrate. Systemic T cell depletion abrogated this regression indicating a T-cell dependent effect. In contrast, when KPC mice bearing spontaneously arising PDA tumors were treated with an agonist CD40 mAb and gemcitabine, a fraction of tumors regressed but in the absence of tumor-infiltrating T cells (mirroring the clinical trial). To determine whether T cells in KPC animals were globally tolerized, KPC mice bearing a spontaneous tumor were challenged with PDA cells subcutaneously. As seen in non-KPC mice, subcutaneously implanted tumors grew exponentially and were found to lack infiltrating T cells. However, when treated with an agonist CD40 mAb and gemcitabine, these implanted tumors exhibited a marked T-cell infiltration leading to regression, suggesting that effector T cells can target PDA in the KPC model. Moreover, treatment of KPC mice bearing both implanted and subcutaneously arising tumors produced an impressive influx of T cells into the primary pancreatic tumors of KPC mice, a finding that was not observed when KPC mice were activated with CD40 mAb and gemcitabine in the absence of the PDA subcutaneous implant. Thus, tumor-reactive T cells in KPC mice are not clonally deleted or globally tolerant to PDA. These data suggest that elements of the tumor microenvironment may mediate local immune suppression that can be overcome by immune priming outside the tumor microenvironment. Our findings have important implications for the design of novel immunotherapy trials in pancreatic cancer, and highlight the opportunity to develop vaccines and other T cell therapies for this disease. Citation Format: Gregory L. Beatty, Rafael Winograd, Rebecca A. Evans, Robert H. Vonderheide. Immune surveillance and CD40 therapy of pancreatic cancer in mice and humans. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr IA9.