CCL2/CCR2-Dependent Recruitment of Functional Antigen-Presenting Cells into Tumors upon Chemotherapy

Abstract

The therapeutic efficacy of anthracyclines relies, at least partially, on the induction of a dendritic cell-and T-lymphocyte-dependent anticancer immune response. Here, we show that anthracycline-based chemotherapy promotes the recruitment of functional CD11bpresenting cells (APC) into the tumor bed, but not into lymphoid organs. Accordingly, draining lymph nodes turned out to be dispensable for the proliferation of tumor antigen-specific T cells within neoplastic lesions as induced by anthracyclines. In addition, we found that tumors treated with anthracyclines manifest increased expression levels of the chemokine Ccl2. Such a response is important as neoplasms growing in Ccl2 À/À mice failed to accumulate dendritic cell-like APCs in response to chemotherapy. Moreover, cancers developing in mice lacking Ccl2 or its receptor (Ccr2) exhibited suboptimal therapeutic responses to anthracycline-based chemotherapy. Altogether, our results underscore the importance of the CCL2/CCR2 signaling axis for therapeutic anticancer immune responses as elicited by immunogenic chemotherapy. Cancer Res; 74(2); 436-45. Ó2013 AACR.

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

“…Here, the crucial mediators have been identified as dying tumor cell-derived ATP, CCL2, and −7, and the authors have not described an initial neutrophil phase. 8,35 Although nucleotides, including ATP, are released from irradiated tumor cells and stimulate chemokinetic monocyte migration in vitro , data from this and our previous study suggest that they fail to induce directional monocyte migration and do not contribute to endothelial cell activation. 27 Nevertheless, they may act as local amplifiers of recruitment signals.…”

“…34 Along these lines, it becomes increasingly evident that monocytic cells can give rise to a population of monocytic APCs which are of importance for the stimulation of anti-tumor immune mechanisms during cancer therapy – at least in mouse tumor models. 8,35,36 For anthracycline-based chemotherapy, it has already been shown that dying cancer cells can stimulate the differentiation of recruited monocytes into antigen-presenting DCs. 8 Thus, we hypothesized that similar effects on DC differentiation and maturation may be induced by irradiated, dying cancer cells.…”

“…Anthracycline-based chemotherapy stimulates intra-tumoral infiltration of Ly6C hi monocytic cells which further differentiate into APCs. 8,35 Additionally, Ly6C hi monocytes per se appear to be able to efferocytose dying tumor cells and cross-present tumor antigens to CD8 + T cells. 50 However, tumor-promoting monocytic myeloid-derived suppressor cells (MDSCs) also share certain phenotypic similarities with inflammatory Ly6C hi monocytes.…”

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

“…Thus, an abnormal HER2 activation such as that occurring in tumors with HER2 amplification could generate an inflammatory environment, as has been described for other oncogenes such as RET/PTC1 in thyroid cancer, 21 RAF in melanoma, and MYC in pancreatic tumors. 22 Considering that the PI3K/AKT pathway is common to different membrane receptors, tumor cell signals other than HER2 may contribute to CCL2 expression albeit to a lesser extent in HER2-addicted BCs.…”

Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

“…21 When emitted in the correct spatiotemporal pattern, [22][23][24] such DAMPs recruit antigen-presenting cells, including dendritic cells, to the site of ICD and activate them to engulf dead cell-associated antigens, process and present them to CD4 C and CD8 C T lymphocytes in the context of co-stimulatory signals, resulting in the priming of a robust, antigen-specific immune response. [25][26][27][28][29][30][31] In line with this notion, the ability of cancer cells undergoing ICD to elicit a protective immune response upon inoculation to syngeneic mice is abrogated: (1) when the molecular pathways underlying the emission of the abovementioned DAMPs are pharmacologically or genetically inhibited in malignant cells; 13,32,33 as well as (2) in mice affected by relatively generalized forms or immunodeficiency or lacking specific components of the DAMP-sensing machinery, such as Toll-like receptor 4 (Tlr4) or type I interferon (a and b) receptor 1 (Ifnar1). 15,21,34 A more detailed description of these signal transduction pathways and cellular circuitries goes beyond the scope of this Trial Watch and can be found in several recent reviews.…”