Τίτλος:
Csf1/csf1r axis blockade limits mesothelioma and enhances efficiency of anti-pdl1 immunotherapy
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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 immuno-suppressive 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. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Συγγραφείς:
Magkouta, S.F.
Vaitsi, P.C.
Pappas, A.G.
Iliopoulou, M.
Kosti, C.N.
Psarra, K.
Kalomenidis, I.T.
Περιοδικό:
Blood cancer journal
Λέξεις-κλειδιά:
antineoplastic agent; blz 945; colony stimulating factor 1; colony stimulating factor receptor; colony stimulating factor receptor 1; programmed death 1 ligand 1; programmed death 1 ligand 1 inhibitor; programmed death 1 receptor; unclassified drug, animal experiment; animal model; animal tissue; antineoplastic activity; Article; cancer growth; cancer immunotherapy; CD8+ T lymphocyte; cell expansion; cell population; clinical effectiveness; controlled study; CSF1 CSF1R signaling; disease burden; flow cytometry; immunofluorescence; immunohistochemistry; in vitro study; lymphocyte subpopulation; M2 tumor-associated macrophage; mesothelioma; mouse; nonhuman; protein expression; RNA sequencing; signal transduction; upregulation
DOI:
10.3390/cancers13112546
