Activation of p53 in Immature Myeloid Precursor Cells Controls Differentiation into Ly6c+CD103+ Monocytic Antigen-Presenting Cells in Tumors

Abstract

CD103 dendritic cells are critical for cross-presentation of tumor antigens. Here we have shown that during immunotherapy, large numbers of cells expressing CD103 arose in murine tumors via direct differentiation of Ly6c monocytic precursors. These Ly6cCD103 cells could derive from bone-marrow monocytic progenitors (cMoPs) or from peripheral cells present within the myeloid-derived suppressor cell (MDSC) population. Differentiation was controlled by inflammation-induced activation of the transcription factor p53, which drove upregulation of Batf3 and acquisition of the Ly6cCD103 phenotype. Mice with a targeted deletion of p53 in myeloid cells selectively lost the Ly6cCD103 population and became unable to respond to multiple forms of immunotherapy and immunogenic chemotherapy. Conversely, increasing p53 expression using a p53-agonist drug caused a sustained increase in Ly6cCD103 cells in tumors during immunotherapy, which markedly enhanced the efficacy and duration of response. Thus, p53-driven differentiation of Ly6cCD103 monocytic cells represents a potent and previously unrecognized target for immunotherapy.

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.…”

“…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.…”

“…51 A recent study provided evidence that antigen-presenting Ly6C hi CD103 + monocytic cells which accumulate intra-tumorally during immunogenic chemotherapy and exert crucial functions as “first responders” in initiating an anti-tumor response can emerge from tumor-resident MDSC as well as from bone-marrow-derived monocytic precursors. 36 Thus, it will be interesting to dissect the differentiation fate and functionality of the Ly6C hi monocytes that were recruited by supernatants of irradiated tumor cells in our model in greater detail, for instance if they – in the course of differentiation – give rise to the Ly6C lo monocytic population which appeared in the air pouches, or if these cells rather are of tissue-resident origin. 52 …”

Alteration of Tumor Metabolism by CD4+ T Cells Leads to TNF-α-Dependent Intensification of Oxidative Stress and Tumor Cell Death

“…In this regard, IFNγ is known to possess potent antivascular effects (Kammertoens et al, 2017; Qin and Blankenstein, 2000). Moreover, some recent studies have revealed novel mechanisms by which T cell-derived IFNγ remodels the TME to promote antitumor immunity (Ayers et al, 2017; Sharma et al, 2018; Wang et al, 2016). Wang et al (2016) reported IFNγ derived from tumor-infiltrating CD8+ T cells can act upon stromal fibroblasts to reduce GSH in the TME, thereby abrogating tumor resistance to chemotherapy.…”

“…Wang et al (2016) reported IFNγ derived from tumor-infiltrating CD8+ T cells can act upon stromal fibroblasts to reduce GSH in the TME, thereby abrogating tumor resistance to chemotherapy. Sharma et al (2018) showed that T cell-derived IFNγ acts upon immature myeloid cells to promote their differentiation into CD103+ immunogenic antigen-presenting cells (APCs) through a p53-dependent mechanism. Here we showed that the host response to IFNγ was required for the curative effect of CTX + CD4 AT treatment (Figure S1B), in line with the notion that IFNγ may contribute to tumor rejection by acting on the TME, including disrupting tumor vasculature, reducing stroma-derived GSH, and promoting immunogenic APCs.…”