Comparison of the Effects of Immunosuppressive Factors from Newly Established Colon Carcinoma Cell Cultures on Human Lymphocyte Proliferation and Cytokine Secretion

Abstract

Tumor cells may influence the host’s immune reactivity by the production of immunosuppressive factors (ISFs). In this study, the effects of ISFs derived from nine polyclonal colorectal carcinoma (CRC) cell lines on PHA-induced lymphocyte proliferation and cytokine secretion was investigated. We found that most of the culture supernatants (8/9) from CRC cell lines contained ISFs, which inhibited T cell proliferation to a variable degree in a dose-dependent manner. Comparison of T cell proliferation in the presence or absence of monocytes showed that monocytes can modulate the effects of tumor-derived ISFs on lymphocyte function. In addition, exposure of activated PBMC to the tumor cell supernatants resulted in an altered secretion of cytokines by these cells, i.e. the secretion of IFN-γ was generally reduced while the secretion of IL-1β, IL-2 and TNF-α was little affected. We further investigated the supernatants’ inhibitory effects on PBMC in respect to the production of prostaglandin E₂ (PGE₂). It was found that PGE₂ was secreted by all tumor cell cultures. Therefore this substance is probably involved in the immunosuppression in vivo. However, the secreted PGE₂ was shown not to be solely responsible for the observed suppression of lymphocyte proliferation in vitro. Our results suggest that the secretion of ISF is a common property of CRCs as demonstrated with newly established CRC cell cultures, and therefore this may also be an important immune escape mechanism of colonic carcinomas in vivo.

Reprogramming the tumor microenvironment: tumor-induced immunosuppressive factors paralyze T cells

“…In vivo studies have shown that PGE2 overexpression results in production of the immunosuppressive cytokine IL-10 and downregulation of the immunostimulatory cytokines IL-12 and IFNg. [169][170][171][172] Further support of the importance of COX2 in inhibiting antitumor immune responses is provided by an in vivo study in which COX2 expression was silenced with antisense oligonucleotides or COX2 activity was blocked with a selective COX2 inhibitor. 173 Knockdown/inhibition of COX2 resulted in increased lymphocyte infiltration, increased levels of IL-12 and IFNg, and decreased levels of IL-10, ultimately reducing tumor burden.…”

“…171,173 Thus, inhibition of COX2 and PGE using COX2 inhibitors may stimulate cellular immunity, resulting in potent antitumor effects. 172 …”

Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor

“…Furthermore, specific inhibition of COX-2 or PGE 2 activity with specific mAb restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis (6). PGE 2 is also reported to downregulate IFN-γ production and might, in principle, thereby interfere with cell-mediated immunity (50,51). Here we demonstrate that absence of the PGE 2 EP2 receptor prevents the inhibition of DC function and allows induction of specific immunity against the tumor.…”

Phase I clinical trial of a TGF-β antisense-modified tumor cell vaccine in patients with advanced glioma

“…Tumors utilize different mechanisms to evade immune surveillance. Many tumors, including gliomas, produce a variety of immunosuppressive molecules including transforming growth factor-b1 (TGF-b1) and TGF-b2 (collectively referred to as TGF-b), [8][9][10] prostaglandin E2, 11 interleukin-6 and -10, 12 and cyclooxygenase-2. 13 Cancer patients frequently demonstrate impaired immune function.…”