High Frequencies of Functional Tumor-Reactive T Cells in Bone Marrow and Blood of Pancreatic Cancer Patients

Friedrich H Schmitz-Winnenthal,Marianna Bucur,Yvonne Ziouta,Philipp Beckhove,Christine Volk,Kaspar Z'Graggen,JüRgen Weitz,Volker Schirrmacher,Daniel Nummer,Markus W BüChler,Luis Galindo

doi:10.1158/0008-5472.can-05-1098

Abstract

Pancreatic cancer is characterized by aggressive growth and treatment resistance. New approaches include immunotherapeutic strategies but the type and extent of spontaneous immune responses against tumor antigens remains unclear. A dominance of TH2 cytokines in patients' sera reported previously suggests systemic tumor-induced immunosuppression, potentially inhibiting the induction of tumor-reactive T cells. We characterized the localization, frequencies, and functional potential of spontaneously induced memory T cells specific for individual tumor antigens or the tumor-associated antigen mucin-1 in the peripheral blood and bone marrow of 41 pancreatic cancer patients. We found high numbers of tumor-reactive T cells in all bone marrow samples and in 50% of the blood samples. These cells secreted the TH1 cytokine IFN-gamma rather than TH2 cytokines upon stimulation with tumor antigens. Although consistently induced during pancreatic cancer, T cells specific for pancreatic antigens were not detected during chronic pancreatitis, suggesting that their evaluation may be of diagnostic use in both diseases. Freshly isolated T cells from cancer patients recognized autologous tumor cells and rejected them in vitro and in a xenotransplant model in vivo, suggesting their therapeutic potential. Thus, tumor antigen-specific T cell responses occur regularly during pancreatic cancer disease and lead to enrichment of tumor cell-reactive memory T cells in the bone marrow. The bone marrow can therefore be considered an important organ for antitumor immune responses in pancreatic cancer.

Highlights

Pancreatic cancer is a highly aggressive, treatment refractory disease and the fourth leading cause of cancer death in the U.S [1]
Allogeneic lysates of pancreatic tumor cells did not induce pronounced cytokine production of T cells from five healthy donors when compared with PBMC lysates from corresponding tumor patients (Fig. 1A), demonstrating that potential differences in cytokine contents between tumor- and PBMC lysates are unlikely to account for differences in spot numbers of patients’ ELISPOT assays
We showed the presence and enrichment of functional tumor-specific T cells in bone marrow and peripheral blood of pancreatic cancer patients, their ability to directly recognize life autologous tumor cells remained unclear

Summary

Introduction

Pancreatic cancer is a highly aggressive, treatment refractory disease and the fourth leading cause of cancer death in the U.S [1]. New approaches which employ the patient’s immune system for treatment may improve survival of pancreatic cancer patients in the future. Pancreatic cancers seem to be capable of immune evasion, immune suppression, or immune modulation. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Pancreatic tumors were shown to secrete immunomodulatory cytokines such as interleukin (IL)-10 and transforming growth factor-h (TGF-h), which are known to suppress TH1 responses and to support TH2 responses that might downregulate CTL activity [1, 6]. Previous studies showed a predominance of TH2 cytokines and TH2 T cells in the blood of pancreatic cancer patients, suggesting a general tumor-induced modulation of cellular immune responses [7]

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Conclusion