Macrophage-Targeted Therapy Unlocks Antitumoral Cross-talk between IFNγ-Secreting Lymphocytes and IL12-Producing Dendritic Cells

Abstract

Macrophages often abound within tumors, express colony-stimulating factor 1 receptor (CSF1R), and are linked to adverse patient survival. Drugs blocking CSF1R signaling have been used to suppress tumor-promoting macrophage responses; however, their mechanisms of action remain incompletely understood. Here, we assessed the lung tumor immune microenvironment in mice treated with BLZ945, a prototypical small-molecule CSF1R inhibitor, using single-cell RNA sequencing and mechanistic validation approaches. We showed that tumor control was not caused by CSF1R+ cell depletion; instead, CSF1R targeting reshaped the CSF1R+ cell landscape, which unlocked cross-talk between antitumoral CSF1R− cells. These cells included IFNγ-producing natural killer and T cells, and an IL12-producing dendritic cell subset, denoted as DC3, which were all necessary for CSF1R inhibitor–mediated lung tumor control. These data indicate that CSF1R targeting can activate a cardinal cross-talk between cells that are not macrophages and that are essential to mediate the effects of T cell–targeted immunotherapies and promote antitumor immunity. See related Spotlight by Burrello and de Visser, p. 4.

Macrophages as tools and targets in cancer therapy

“…Several studies in preclinical models proved that CSF1R inhibition reduced the density of TAMs and tumour growth, and increased the sensitivity to chemotherapy 5 , 110 , 112 , 113 . Although the small-molecule inhibitor BLZ945 did not deplete TAMs, these underwent a reprogramming towards an antitumour phenotype 112 , 114 ; upon CSF1R blockade, macrophages showed lower expression of pro-tumorigenic genes and upregulation of genes associated with antigen presentation and lymphocyte activation. BLZ945 reshaped the immune microenvironment inducing positive crosstalk among TAMs, IFNγ-producing NK and T cells, and IL-12-producing dendritic cells, thus sustaining a virtuous network of antitumour responses 114 .…”

“…Although the small-molecule inhibitor BLZ945 did not deplete TAMs, these underwent a reprogramming towards an antitumour phenotype 112 , 114 ; upon CSF1R blockade, macrophages showed lower expression of pro-tumorigenic genes and upregulation of genes associated with antigen presentation and lymphocyte activation. BLZ945 reshaped the immune microenvironment inducing positive crosstalk among TAMs, IFNγ-producing NK and T cells, and IL-12-producing dendritic cells, thus sustaining a virtuous network of antitumour responses 114 . Inhibition of CSF1R in patients with a rare tumour (diffuse-type tenosynovial giant cells) overexpressing CSF1 led to significant clinical benefit in 71% of patients in the study 115 .…”

Targeting tumor-associated macrophages for successful immunotherapy of ovarian carcinoma

“…111 Blocking the CSF1-CSF1R axis with mAbs or tyrosine kinase inhibitors can either reduce TAM numbers or alter their tumor-promoting features and thus reduce tumor progression in numerous experimental models (eg, lung carcinoma, glioma and fibrosarcoma). [112][113][114] Administration of GW2580, a CSF1R inhibitor (CSF1Ri), reduced the infiltration of M2-like TAMs, increased the proportion of M1-like TAMs expressing CCR2, IL-12, and IFN-γ, on March 5, 2023 by guest. Protected by copyright.…”

In Vivo Click Chemistry Enables Multiplexed Intravital Microscopy

“…This in turn leads to local IL‐12 upregulation in target cells with antineoplastic effects based on immune cell regulation [ 27,31,32 ] as part of a larger effort to induce local [ 33 ] rather than systemic IL‐12. [ 34 ] Up to now, what was unknown in this paradigm was the specific cell type in which CDNPs localize in the GBM microenvironment. To study this effect we used a Mer‐TK mouse model [ 35 ] in which all macrophages contain GFP and implanted CT2a tumor cells tagged with H2B‐apple in a cranial window chamber.…”

“…This in turn leads to local IL-12 upregulation in target cells with antineoplastic effects based on immune cell regulation [27,31,32] as part of a larger effort to induce local [33] rather than systemic IL-12. [34] Up to now, what was unknown in this paradigm was the specific cell type in which CDNPs localize in the GBM microenvironment.…”