Anticancer Chemotherapy-Induced Intratumoral Recruitment and Differentiation of Antigen-Presenting Cells

Abstract

The therapeutic efficacy of anthracyclines relies on antitumor immune responses elicited by dying cancer cells. How chemotherapy-induced cell death leads to efficient antigen presentation to T cells, however, remains a conundrum. We found that intratumoral CD11c(+)CD11b(+)Ly6C(hi) cells, which displayed some characteristics of inflammatory dendritic cells and included granulomonocytic precursors, were crucial for anthracycline-induced anticancer immune responses. ATP released by dying cancer cells recruited myeloid cells into tumors and stimulated the local differentiation of CD11c(+)CD11b(+)Ly6C(hi) cells. Such cells efficiently engulfed tumor antigens in situ and presented them to T lymphocytes, thus vaccinating mice, upon adoptive transfer, against a challenge with cancer cells. Manipulations preventing tumor infiltration by CD11c(+)CD11b(+)Ly6C(hi) cells, such as the local overexpression of ectonucleotidases, the blockade of purinergic receptors, or the neutralization of CD11b, abolished the immune system-dependent antitumor activity of anthracyclines. Our results identify a subset of tumor-infiltrating leukocytes as therapy-relevant antigen-presenting cells.

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

“…8,36 This is in accordance with our in vitro observations with human monocytes whose differentiation into DCs, maturation, and predominantly the upregulation of CD80 and CD86 was enhanced in the presence of supernatants of irradiated tumor cells. Functionally, this was paralleled by improved stimulation of allogeneic CD8 + , and to a lesser extent also CD4 + T cells with the strongest effects seen with supernatants of 20 Gy-irradiated tumor 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.…”

“…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.…”