Apoptotic tumor cells induce IL‐27 release from human DCs to activate Treg cells that express CD69 and attenuate cytotoxicity

Abstract

Summary Intrinsic immunosuppression is a major obstacle for a successful cancer therapy. Mechanisms how immunosuppression is induced and regulated in humans are ill-defined. A micro-environmental component that might prevent anti-tumor immunity is the presence of dying tumor cells, which is abundant following conventional cancer ablation methods such as chemo- or radiotherapy. Shedding of apoptotic debris and/or secretion of factors to the tumor bed or draining lymph nodes thus might have a profound impact on professional phagocytes such as DC and subsequent priming of lymphocytes. In this study, we exposed human DC to supernatants of living, apoptotic or necrotic human breast cancer cells and co-cultured them with autologous T cells. Priming with apoptotic debris prevented DC from establishing cytotoxicity towards living human tumor cells by inducing a regulatory T cell population, defined by co-expression of CD39 and CD69. Immunosuppression via Treg was transferable and required the release of sphingosine-1-phosphate (S1P) from apoptotic cells, acting via S1P receptor 4 on DC to induce IL-27 secretion. We propose that CD69-expression on CD39+ Treg enables them to interact with CD73-expressing CD8+ T cells to generate adenosine, thereby suppressing cytotoxicity. These findings aid the understanding how dying tumor cells limit anti-tumor immunity.

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

“…Previous studies have reported that IL-27 receptor knock-out down-modulates the expression of CD39 on dendritic cells and regulatory T cells. 52,53 LPS-stimulated human monocytes produce IL-27 ( Fig. S5A) and LPSstimulated macrophages expressed the transcript encoding IL-27, IL-27RA and gp130 (data not shown).…”

Clinical Implications of the Interleukin 27 Serum Level in Breast Cancer

“…Sekar et al 18 have shown that apoptotic tumor cells prevent dendritic cells from establishing cytotoxicity toward living human tumor cells by inducing IL-27, thus stimulating a Treg cell population. This is the possible mechanism by which cancer patients in general may have increased levels of IL-27.…”

Induction of antigen specific CD4+CD25+Foxp3+T regulatory cells from naïve natural thymic derived T regulatory cells

“…IL-27 induces CD39 + CD69 + Treg that inhibit anti-tumor CD73 + cytotoxic T cells to produce adenosine, that inhibit the effector T cells [183] and NK cells through adenosine receptor 2A [184]. IL-27 knockout mice have less Treg probably due to reduced IL-2 production [185].…”