Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells

Abstract

In cancer patients, immunosuppression through regulatory T cells (Treg) is a crucial component of tumor immune evasion and contributes to disease progression. Tumor-infiltrating Treg in particular suppress local effector T cell responses and are associated with poor prognosis in tumors such as human pancreatic cancer or hepatocellular carcinoma (HCC). The chemokine CCL22 is known to recruit Treg into the tumor tissue and many types of human tumors are known to express high levels of CCL22. The mechanisms leading to intratumoral secretion of CCL22 are so far unknown. We demonstrate here that intratumoral CCL22 is induced in tumor-infiltrating immune cells through cancer cell-derived interleukin-1 (IL-1a). In pancreatic cancer and HCC, CCL22 is produced by intratumoral dendritic cells, while the cancer cells themselves do not secrete CCL22 in vitro and in vivo. Incubation of human peripheral blood mononuclear cells (PBMC) or murine splenocytes with tumor cells or tumor cell supernatants strongly induced CCL22 secretion in vitro. Tumor cell supernatants contained IL-1 and CCL22 induction in PBMC could be specifically prevented by the IL-1 receptor antagonist anakinra or by transfection of tumor cell lines with IL-1 siRNA, leading to a suppression of Treg migration. In conclusion, we identify here tumor cell-derived IL-1a as a major inducer of the Treg attracting chemokine CCL22 in human cancer cells. Therapeutic blockade of the IL-1 pathway could represent a promising strategy to inhibit tumorinduced immunosuppression.

Ionizing radiation modulates the phenotype and function of human CD4+ induced regulatory T cells

“…While the most effective immunotherapies in development seek to generate, promote, or stimulate tumorspecific CTLs, tumors often induce an immunosuppressive microenvironment that allows them to evade immune cell killing [4]. A major mechanism of tumorinduced immunosuppression is the recruitment and/or induction of CD4+ regulatory T cells (T REGS ) within the tumor microenvironment [5,6].…”

Deciphering and Reversing Immunosuppressive Cells in the Treatment of Hepatocellular Carcinoma

“…46 The recruitment of Tregs in HCC occurs via the CCR6-CCL20 axis 47 and CCL22 induction by tumor cell-secreted IL-1α. 48 FoxP3 is not only essential for development of Tregs but also remains the best marker to identify these cells. However, several studies have shown that activation of human non-Tregs can also lead to expression of FoxP3 in vitro , suggesting that this marker needs to be used with caution.…”

Ping-Pong—Tumor and Host in Pancreatic Cancer Progression

“…DC maturation and activation is also hindered by confrontation with immunosuppressive cytokines TGFß, IL6, IL10, and GM-CSF, which activate the STAT3 pathway (693)(694)(695). Furthermore, costimulatory molecule CD40 and CD80 expression is reduced in DC, hampering T-cell activation (696). Instead, DC produce CCL22, which recruits Treg (697, 698).…”