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.

Functionalized Nanoparticles Targeting Tumor-Associated Macrophages as Cancer Therapy

“…The survival, proliferation and function of TAMs depend to a large extent on CSF-1R signaling ( Figure 4 ). Blocking the CSF-1-CSF-1R axis inhibits the polarization of macrophages, thereby reducing tumor cell proliferation and inducing TAM apoptosis [ 73 ] ( Figure 4 ). Many preclinical studies demonstrated high efficacies of CSF-1R inhibitors.…”

Mesothelioma Malignancy and the Microenvironment: Molecular Mechanisms

“…Accordingly, in vitro and in vivo studies have demonstrated that inhibition of CSF-1R might restore the CD8 + T cell anti-tumor response [ 98 , 100 ]. Inhibition of CSF-1R not only avoided mesothelioma progression and enhanced T cell response, but was also shown to increase the sensitivity of mesothelioma to PD-L1 inhibitors [ 101 ]. Additionally, in vivo studies have demonstrated the efficacy of a recently developed monoclonal antibody anti-CSF-1R (RG7155) in the reduction of CD68 + /CD163 + TAMs in mesothelioma biopsies [ 102 ].…”

“…The presence of M-CSF and IL-34 was associated with short survival and chemoresistance [ 98 , 99 ]. Recently, the inhibition of CSF-1R has been shown to reduce mesothelioma progression and increase the susceptibility of MPM to immune checkpoint inhibitors [ 101 ]. The activation of the IL-1β/IL-1R signaling pathway in tumors by TAMs is correlated with the acquisition of a CSC-like phenotype [ 96 ].…”

Colony Stimulating Factor-1 and its Receptor in Gastrointestinal Malignant Tumors

“…CSF-1/CSF-1R signaling mediates tumor-associated macrophages recruitment and M2 polarization. In experimental mesotheliomas, combined a highly selective small molecule CSF-1R inhibitor-BLZ945 with an anti-PDL1 agent was more effective in retarding tumor growth compared to each monotherapy 58 . Moreover, AMG 820, an anti-CSF-1R antibody, showed acceptable safety profile in combination with pembrolizumab in adults with advanced solid tumors by reducing CSF-1 dependent CD16 expressing monocytes, and increasing PD-L1 expression and infiltrating T-lymphocyte numbers in advanced solid tumor biopsies 57 .…”

“…However, numerous recent studies have found that CSF-1/CSF-1R axis blockade can improve the efficiency of immune checkpoint inhibitors, especially PD-L1. Thus, in terms of tumor control, the combination therapy targeting CSF-1/CSF-1R axis and immune checkpoint molecular has more reliable efficacy 57 , 58 . CSF-1/CSF-1R signaling mediates tumor-associated macrophages recruitment and M2 polarization.…”