Abstract
Simple SummaryCSF1/CSF1R signaling mediates tumor-associated macrophages recruitment and M2 polarization. M2 TAMs are dominant immune populations infiltrating mesothelioma tumors. We evaluated the role of CSF1/CSF1R axis blockade in tumor-infiltrating immune subsets. We also examined the effect of combined anti-CSF1R and anti-PDL1 treatment in mesothelioma progression. We show that CSF1R inhibition impedes mesothelioma progression, abrogates infiltration of TAMs, facilitates an M1 anti-tumor phenotype and activates tumor dendritic and CD8+ T cells. We also show that this inhibitor was able to significantly improve the effectiveness of anti-PDL1 immunotherapy.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.
Highlights
Malignant pleural mesothelioma is the most common primary pleural tumor with an increasing global incidence and dismal prognosis [1]
The above data argue against an autocrine or paracrine impact of the Colony-Stimulating Factor 1 (CSF1)/CSF1R axis on tumor cells themselves
(3) In human mesotheliomas: (a) tumor CSF1R expression mainly occurs in tumor-associated macrophage (TAM), and it is linked with advanced stages of the disease. (b) Abundance of infiltrating CD8 lymphocytes is associated with better prognosis only in low CSF1R-expressing tumors
Summary
Malignant pleural mesothelioma is the most common primary pleural tumor with an increasing global incidence and dismal prognosis [1]. Tumor-Associated Macrophages (TAMs) present the dominant innate immune population of the mesothelioma inflammatory tumor infiltrate [10], and they are mainly M2polarized [11] and highly immunosuppressive, with >75% of them expressing PDL1, consisting the main source of PDL1 in a tumor microenvironment [10]. Colony-Stimulating Factor 1 (CSF1)/Colony-Stimulating Factor Receptor (CSF1R) signaling plays important role in the recruitment of monocytes into mesothelioma tumors, their differentiation into M2-like macrophages [11,12], impaired CD8 T cell cytotoxicity [12] and chemoresistance [11,13]. Abundant macrophage infiltration [14,15], CSF1 pleural levels [12] and PDL1 expression [16] have been linked to poor prognosis of mesothelioma patients. We hypothesized that CSF1/CSF1R inhibition would limit mesothelioma progression by targeting immunosuppressive macrophages. We hypothesized that CSF1/CSF1R blockade would enhance the efficacy of PDL1 inhibitor
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