Blogs

Targeted release of a bispecific fusion protein SIRPα/Siglec-10 by oncolytic adenovirus reinvigorates tumor-associated macrophages to improve therapeutic outcomes in solid tumors

Summary:
 

Finding ways to promote phagocytosis, antigen processing, and delivery and activation of antigen-specific CD8⁺ T cells by largely immunosuppressive tumor-associated macrophages (TAMs) has been a long-standing goal. Efforts to block the “don’t eat me” signal of CD47 on tumors have been less successful than originally hoped, given its expression on red cells and platelets, and thus causing toxicity. SIRPα is the negative signaling polymorphic CD47 counter-receptor expressed on macrophages, neurons, and dendritic cells. Similarly, expression of the inhibitory receptor sialic-acid-binding immunoglobulin-like lectin 10 (Siglec-10) on macrophages diminishes phagocytosis of tumor cells expressing CD24. Production and delivery of a novel SIRPα-Siglec-10 fusion protein delivered directly into the tumor by an oncolytic adenovirus thus allowed dual stimulation of phagocytosis. This enhanced activation and expression of CD86, IFNγ, TNF, IL-1β, IRF7, and decreased expression of CD206, IL-10, Arg1, TGFβ, VEGF, and immunosuppressive inducible nitric oxide synthase (iNOS). Following delivery in vivo, the authors were able to drive the elimination of four individual murine tumors that they tested, as well as a human tumor in a humanized model.

β-blocker suppresses both tumoral sympathetic neurons and perivascular macrophages during oncolytic herpes virotherapy (oHV)

Consistent with the theme for this month of the intersection of Neuro- and Immunobiology, efforts to tie sympathetic blockade to enhancing tumor immunity were studied in breast cancer. Not only do virtually all patients with breast cancer demonstrate expression of neuronal markers, including TUBB3, but also adrenergic receptors ADRB2 found on T, B, NK, and dendritic cells, and macrophages. Here they also demonstrated promotion of inflammatory macrophages and enhanced diversity of T cells within tumors with combination therapy in murine models of oHV coupled with administration of a β-blocker. With injection of oHV, and additively with a β-blocker, the authors demonstrated synergistic antitumor activity associated with enhanced T cell infiltrate as well as decreased TGFβ expression. 

LILRB2 blockade facilitates macrophage repolarization and enhances T cell-mediated antitumor immunity

LILRB2 — also known as immunoglobulin-like transcript 4 (ILT4); CD85D; monocyte/macrophage immunoglobulin-like receptor 10 (MIR10); and leukocyte immunoglobulin-like receptor 2 (LIR2) — is expressed on most myeloid cells.  Remarkably, another macrophage-targeting strategy was developed here, demonstrating that a novel antibody that they generated blocked its expression on TAMs. This in turn promoted CD40L-stimulated myeloid proinflammatory cytokine production (GM-CSF and TNF) and enhanced the ability to stimulate antigen-specific T cells. Furthermore, its application had single-agent antitumor effects alone and synergistically in combination with an anti-PD1 antibody in murine models. 

Neural crest-associated gene FOXD1 induces an immunosuppressive microenvironment by regulating myeloid-derived suppressor cells in melanoma

Summary: 

The neural crest-associated gene Forkhead Box D1 (FOXD1), expressed in melanoma, was studied as to its effects on melanoma-associated macrophages. Interestingly, the authors demonstrated that expression of this gene product in melanoma cells drives production of interleukin-6 (IL-6). This in turn promotes recruitment of myeloid-derived suppressor cells (MDSC) as well as Tregs. MDSC produce the iNOS, arginase 1, IL-10, and COX-2, as well as express the checkpoint receptor PD-L1. Knockdown of FOXD1 or its inhibition with miR-581, which the study identifies, limited MDSC infiltration as well as IL-6 production. In FOXD1 overexpressing cell lines, tumor growth was enhanced and its ablation in immune competent mice limited tumor growth, but interestingly had no effect in immune incompetent mice.