RedirectingIn vivoElicited Tumor Infiltrating Macrophages and Dendritic Cells towards Tumor Rejection

Abstract

A hostile tumor microenvironment interferes with the development and function of the adaptive immune response. Here we report the mechanisms by which large numbers of tumor-infiltrating macrophages and dendritic cells (DC) can be redirected to become potent effectors and activators of the innate and adaptive immunity, respectively. We use adenoviral delivery of the CCL16 chemokine to promote accumulation of macrophages and DC at the site of preestablished tumor nodules, combined with the Toll-like receptor 9 ligand CpG and with anti-interleukin-10 receptor antibody. CpG plus anti-interleukin-10 receptor antibody promptly switched infiltrating macrophages infiltrate from M2 to M1 and triggered innate response debulking large tumors within 16 hours. Tumor-infiltrating DC matured and migrated in parallel with the onset of the innate response, allowing the triggering of adaptive immunity before the diffuse hemorrhagic necrosis halted the communication between tumor and draining lymph nodes. Treatment of B6>CXB6 chimeras implanted with BALB/c tumors with the above combination induced an efficient innate response but not CTL-mediated tumor lysis. In these mice, tumor rejection did not exceed 25%, similarly to that observed in CCR7-null mice that have DC unable to prime an adaptive response. The requirement of CD4 help was shown in CD40-KO, as well as in mice depleted of CD4 T cells, during the priming rather than the effector phase. Our data describe the critical requirements for the immunologic rejection of large tumors: a hemorrhagic necrosis initiated by activated M1 macrophages and a concomitant DC migration to draining lymph nodes for subsequent CTL priming and clearing of any tumor remnants.

Convergent pathways of macrophage polarization: The role of B cells

“…Based on the M1 versus M2 paradigm of macrophage polarization [6], inhibition of M2-and activation of M1-inducing signals (e.g. IL-10 and CpG, respectively) was proposed as a possible strategy to restore the anti-tumor functions of TAM [7,8]. Recent investigations suggest that during tumor growth both innate and adaptive immune cells participate in guiding the pro-tumoral phenotype of TAM [9].…”

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

“…Tumor-associated macrophages constitutively express IL-10 [34], thus maintaining an impaired immune status. We and others [35,36] have reported that IL-10 receptor blockade, when combined with TLR agonists and/or other immunostimulatory agents, rescue the functional paralysis of tumor-infiltrating DCs and macrophages toward an efficient cancer therapy. However, macrophages are not the sole IL-10 source in tumors.…”

“…Conversely, in a murine tumor model, others have shown that CD25 1 -cell depletion and IL-10 receptor blockade exert distinct, though partially overlapping, effects in suppressing DC activation and anti-tumor CD8 1 response [13]. Even if a Foxp3-directed, rather than CD25-directed, Treg-cell depletion may provide more reliable results about the functional redundancy of Treg cells and IL-10, it is likely that Treg cells are not the only source of IL-10 at the tumor site [13] and that sole IL-10 receptor blockade cannot recapitulate the efficient anti-tumor activity of combination therapies [35,36], of the sole OX40 triggering [3,21] or of Foxp3-targeted Treg-cell depletion, when combined to vaccination [39] or even as single treatment [40].…”

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3+ Treg

“…Likewise, TIDC in non-glioma tumors have been described as playing several roles in the anti-tumor response. In hepatocarcinoma and colon carcinoma, functional impairment of TIDC can be reversed by IL-10 neutralization combined with CpG stimulation [34,35]. In contrast, melanoma-derived TIDC are potent APC and can mediate tumor rejection without prior re-stimulation [36].…”