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CSF1/CSF1R Axis Blockade Limits Mesothelioma and Enhances Efficiency of Anti-PDL1 Immunotherapy.

ABSTRACT: Colony-Stimulating Factor 1 (CSF1)/Colony-Stimulating Factor Receptor 1 (CSF1R) signaling orchestrates tumor-associated macrophage (TAM) recruitment and polarization towards a pro-tumor M2 phenotype, the dominant phenotype of TAMs infiltrating mesothelioma tumors. We hypothesized that CSF1/CSF1R inhibition would halt mesothelioma growth by targeting immunosuppressive M2 macrophages and unleashing efficient T cell responses. We also hypothesized that CSF1/CSF1R blockade would enhance the efficacy of a PDL1 inhibitor which directly activates CD8+ cells. We tested a clinically relevant CSF1R inhibitor (BLZ945) in mesothelioma treatment using syngeneic murine models. We evaluated the role of CSF1/CSF1R axis blockade in tumor-infiltrating immune subsets. We examined the effect of combined anti-CSF1R and anti-PDL1 treatment in mesothelioma progression. CSF1R inhibition impedes mesothelioma progression, abrogates infiltration of TAMs, facilitates an M1 anti-tumor phenotype and activates tumor dendritic and CD8+ T cells. CSF1R inhibition triggers a compensatory PD-1/PDL1 upregulation in tumor and immune cells. Combined CSF1R inhibitor with an anti-PDL1 agent was more effective in retarding mesothelioma growth compared to each monotherapy. In experimental mesotheliomas, CSF1R inhibition abrogates tumor progression by limiting suppressive myeloid populations and enhancing CD8+ cell activation and acts synergistically with anti-PDL1.

SUBMITTER: Magkouta SF

PROVIDER: S-EPMC8196870 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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CSF1/CSF1R Axis Blockade Limits Mesothelioma and Enhances Efficiency of Anti-PDL1 Immunotherapy.

Magkouta Sophia Fotiou SF Vaitsi Photene Christou PC Pappas Apostolos Georgiou AG Iliopoulou Marianthi M Kosti Chrysavgi Nikolaou CN Psarra Katherina K Kalomenidis Ioannis Theodorou IT

Cancers 20210522 11

Colony-Stimulating Factor 1 (CSF1)/Colony-Stimulating Factor Receptor 1 (CSF1R) signaling orchestrates tumor-associated macrophage (TAM) recruitment and polarization towards a pro-tumor M2 phenotype, the dominant phenotype of TAMs infiltrating mesothelioma tumors. We hypothesized that CSF1/CSF1R inhibition would halt mesothelioma growth by targeting immunosuppressive M2 macrophages and unleashing efficient T cell responses. We also hypothesized that CSF1/CSF1R blockade would enhance the efficacy ...[more]

PMID: 34067348

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Project description:Among the numerous immune interactions, or lack-thereof, that occur during cancer progression, tumor-associated macrophages (TAMs) - cancer cell interactions have been shown to play an important role in modulating the tumor-microenvironment to an immune suppressive mode, promoting accelerated tumor growth, survival and metastatic spread. TAMs are predominantly polarized to a pro-tumorigenic M2-phenotype through macrophage colony stimulating factor 1 (MCSF) cytokines that bind to the colony-stimulating factor 1 receptor (CSF1R), a class III receptor tyrosine kinase. This MCSF-CSF1R interaction results in autophosphorylation of CSF1R and subsequent phosphorylation and activation of downstream signaling pathways including mitogen-activated protein kinase (MAPK) pathway leading to proliferation, survival and functional activity of M2 TAMs. Therapeutic inhibition of CSF1R and MAPK signaling could effectively re-polarize M2 macrophages to an anti-tumorigenic M1 phenotype; however, this is challenging. In this study, we demonstrate that concurrent and sustained inhibition of the CSF1R and MAPK signaling pathways using dual-kinase inhibitor-loaded supramolecular nanoparticles (DSNs) enhance repolarization of pro-tumorigenic M2 macrophages to the anti-tumorigenic M1 phenotype. The supramolecular nanoparticles exhibited physical stability of over 7 days during storage conditions at 4 °C and over 24 h in human serum, released the inhibitors in a sustained manner and showed significantly higher internalization and accumulation of inhibitors in the M2 macrophages even at longer time points. When tested in a highly aggressive 4T1 breast cancer model, the supramolecular nanoparticles accumulated in TAMs at a significantly higher concentration, increased M1-like phenotype at significantly higher proportion and improved anti-tumor efficacy as compared to combination of single-inhibitor nanoparticles or the small molecule inhibitors. Our data suggests that concurrent, vertical inhibition of multiple intracellular kinase signaling pathways is important for repolarization of M2 macrophages to M1 phenotype, and by utilizing dual-inhibitor loaded supramolecular nanoparticles, further increase the ability to produce more M1 macrophages as compared to M2 macrophages in the tumor microenvironment. This results in enhanced tumor growth inhibition and reduced toxicity. Therefore, vertical, co-inhibition of CSF1R and downstream signaling pathways like MAPK could be a promising macrophage immunotherapy strategy for aggressive cancers.

Dataset Information

CSF1/CSF1R Axis Blockade Limits Mesothelioma and Enhances Efficiency of Anti-PDL1 Immunotherapy.

Publications

CSF1/CSF1R Axis Blockade Limits Mesothelioma and Enhances Efficiency of Anti-PDL1 Immunotherapy.

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