Carcinoembryonic Antigen-Specific but Not Antiviral CD4+ T Cell Immunity Is Impaired in Pancreatic Carcinoma Patients

Abstract

Pancreatic carcinoma is a very aggressive disease with dismal prognosis. Although evidences for tumor-specific T cell immunity exist, factors related to tumor microenvironment and the presence of immunosuppressive cytokines in patients’ sera have been related to its aggressive behavior. Carcinoembryonic Ag (CEA) is overexpressed in 80–90% of pancreatic carcinomas and contains epitopes recognized by CD4+ T cells. The aim of this study was to evaluate the extent of cancer-immune surveillance and immune suppression in pancreatic carcinoma patients by comparing the anti-CEA and antiviral CD4+ T cell immunity. CD4+ T cells from 23 normal donors and 44 patients undergoing surgical resection were tested for recognition of peptides corresponding to CEA and viral naturally processed promiscuous epitopes by proliferation and cytokine release assays. Anti-CEA CD4+ T cell immunity was present in a significantly higher number of normal donors than pancreatic cancer patients. Importantly, whereas CD4+ T cells from normal donors produced mainly GM-CSF and IFN-γ, CD4+ T cells from the patients produced mainly IL-5, demonstrating a skew toward a Th2 type. On the contrary, the extent of antiviral CD4+ T cell immunity was comparable between the two groups and showed a Th1 type. The immunohistochemical analysis of tumor-infiltrating lymphocytes showed a significantly higher number of GATA-3+ compared with T-bet+ lymphoid cells, supporting a Th2 skew also at the tumor site. Collectively, these results demonstrate that Th2-immune deviation in pancreatic cancer is not generalized but tumor related and suggests that the skew might be possibly due to factor(s) present at the tumor site.

Clinical implications of systemic inflammatory response markers as independent prognostic factors for advanced pancreatic cancer

“…The P value was determined using the log-rank test. [23,24]. Increased serum levels of a range of inflammatory cytokines are also associated with clinical features of pancreatic cancer, such as poor performance status, cachexia and overall survival [25,26].…”

Basophil Recruitment into Tumor-Draining Lymph Nodes Correlates with Th2 Inflammation and Reduced Survival in Pancreatic Cancer Patients

“…24. The following antibodies were used: anti-pro-MBP1 (BioLegend, clone J175-7D4), anti-T-bet (Santa Cruz Biotechnology, Inc.), anti-GATA-3 (R&D Systems), anti-CD11c (Novocastra, NCL-CD11c-536), and anti-CD14 (Novocastra).…”

Expansion of Tumor-reactive T Cells From Patients With Pancreatic Cancer

“…14,15 Evasion from immune surveillance has been described in PDAC, including "trapping" of TILs by a dense collagen network, 16 reduced immune effector functions of T cells in peripheral blood, 17 and production of TGF-b 18 along with a Th2 cytokine profile. [19][20][21] A more comprehensive analysis of PDAC TILs has not yet been reported. TILs have been reported in tumors of many histologies, for example, ovarian cancer, 22,23 colorectal cancer, 24,25 or lung cancer, 26 where CD8 + T cells appeared to be more frequent.…”