Abstract PR4: Restoring T cell immuno-surveillance in pancreatic carcinoma using CD40 agonists.
Authors: Beatty Gregory L. , Winograd Rafi , Evans Rebecca , Luque Santiago Lombo , Guirnalda Patrick , Vonderheide Robert H. 
Published: August 2014

Abstract
A hallmark of the tumor microenvironment in pancreatic ductal adenocarcinoma (PDA) is a profound immune infiltrate dominated by myeloid cells with a scarcity of T cells. Immune suppression imposed by this early immune reaction to PDA represents a significant clinical challenge to T cell immunotherapy. To circumvent this immune suppression, we have studied CD40 agonists for their well-recognized ability to induce potent T cell dependent anti-tumor immunity. However, in our studies using the KPC mouse model of PDA (KrasG12D/+ Trp53R172H/+ Pdx-1 Cre), we have found that delivery of a CD40 agonist alone or in combination with chemotherapy is unable to induce productive T cell immunosurveillance. Here, we examine barriers to the development of anti-tumor T cell immunity in PDA. By transplanting PDA tumor cells or whole PDA tumor tissue obtained from tumor-bearing KPC mice into syngeneic littermates, we demonstrate that a CD40 agonist (FGK45) in combination with gemcitabine chemotherapy can synergize to induce productive anti-tumor immunity leading to complete and sustained regression of established subcutaneous tumors (IgG2a alone – 0%; gemcitabine alone – 0%; FGK45 alone – 38%; gemcitabine + FGK45 – 71%; p &lt; 0.001). In contrast to our findings in the KPC model, depletion of either CD4 (GK1.5) or CD8 (2.43) T cells abolished this effect (IgG2a alone – 0%; gemcitabine + FGK45 – 75%; gemcitabine + FGK45 + GK1.5 – 0%; gemcitabine + FGK45 + 2.43 – 14%; p &lt;0.001). This observation suggested that PDA cells retain their immunogenicity and are capable of being recognized and targeted by T cells. To examine the ability of combination therapy (gemcitabine + FGK45) to induce T cell dependent anti-tumor immunity against spontaneously arising PDA, KPC mice treated with combination therapy were challenged subcutaneously two weeks later with PDA cells. However, no immune protection to tumor challenge was observed suggesting a failure to induce tumor-specific T cell immunity. To determine whether systemic immune suppression within KPC mice may inhibit the ability to induce productive T cell immunity, we next transplanted PDA tumor cells subcutaneously into KPC mice with ultrasound-confirmed PDA tumors. We found that combination therapy (gemcitabine + FGK45) delivered to these KPC mice bearing two tumors (i.e. implanted tumor plus a spontaneously arising PDA tumor) could elicit an anti-tumor T cell immune response capable of inducing tumor regression of the subcutaneously implanted tumor (Control – 0%; gemcitabine + FGK45 – 100%; p &lt;0.001). Moreover, by delivering combination therapy to KPC animals in this “two tumor” system, we observed by immunohistochemistry an unprecedented and robust T cell infiltrate, comprised of both CD4 and CD8 T cells, into the spontaneously arising PDA tumor. Our findings suggest that ineffective T cell priming rather than immunoediting may limit T cell immunosurveillance in PDA – a finding that has important implications into the design of cancer immunotherapy for this disease.
This abstract is also presented as Poster B84.
Citation Format: Gregory L. Beatty, Rafi Winograd, Rebecca Evans, Santiago Lombo Luque, Patrick Guirnalda, Robert H. Vonderheide. Restoring T cell immuno-surveillance in pancreatic carcinoma using CD40 agonists. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr PR4.