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

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-; 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. (Cancer Res 2005; 65(21): 10079-87)

Downregulation of CD4+CD25+ regulatory T cells may underlie enhanced Th1 immunity caused by immunization with activated autologous T cells

“…Th1 cells play an important role in anti-tumor immune responses by producing a panel of cytokines such as IFNγ and TNFα [1,2]. IL-12 enhances Th1 cell polarization, leading to more IFNγ and TNFα production.…”

“…It is well known that CD4+ T cells (also called Th1 cells) play an important role in anti-tumor immune responses [1].…”

“…IL-12, produced mainly by monocytes, enhances Th1 immune response [1,2]. Through cytokine productions, Th1 cells synergize with CD8+ T cells (called CTL) in their anti-tumor function.…”

An ISCOM vaccine combined with a TLR9 agonist breaks immune evasion mediated by regulatory T cells in an orthotopic model of pancreatic carcinoma

“…Tumor size was measured three times weekly and determined by the product of perpendicular diameters. Mice were euthanized when the tumor size exceeded 200 mm 2 or with the appearance of distress.…”

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

“…2,21–25 This polyvalent T cell pool consists of effector and central T mem cells, which produce IFN-γ upon Ag re-encounter and can eliminate autologous tumor cells. 26–28 However, there is increasing evidence that tumor-associated immune suppression can be mediated in an Ag-specific manner, too. Our group has previously shown that TA-specific T reg cells are present in cancer patients, which can suppress the proliferation of polyclonally activated conventional T cells (T con cells) and inhibit TA-specific effector T cell responses in vitro .…”