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

Our plain-English summary of CSF1/CSF1R Axis Blockade Limits Mesothelioma and Enhances Efficiency of Anti-PDL1 Immunotherapy, by S.F. Magkouta, P.C. Vaitsi, A.G. Pappas, et al (Cancers, 2021).

The study

• Authors: S.F. Magkouta, P.C. Vaitsi, A.G. Pappas, M. Iliopoulou, C.N. Kosti, K. Psarra, I.T. Kalomenidis
• Journal: Cancers
• Published: 2021;13(11)
• Cited by: 47 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a laboratory study in mice, with added cell-culture work and an analysis of public human tumor data. It did not study asbestos exposure. The authors placed mouse mesothelioma cells (AE17 and AB1) into the chest cavity of mice and gave some mice BLZ945, a drug that blocks a receptor called CSF1R found on immune cells called macrophages. In other experiments mice also received an antibody against PDL1, alone or with BLZ945. In treated mice, BLZ945 reduced tumor burden and pleural fluid, reduced tumor macrophages, and increased the number and activation of CD8 T cells. It did not affect tumor cell survival in the dish. BLZ945 also raised PDL1 levels on tumor cells. The combined treatment was more potent than either drug alone. In data from 88 human mesothelioma tumors, CSF1R gene levels were not associated with survival. Higher CD8 levels were linked with better prognosis only in tumors with low CSF1R levels. The authors said these human observations do not permit definite conclusions. They concluded that in mice the combination was more effective than either drug alone.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment using two mouse (syngeneic) mesothelioma models, with in vitro cell studies and an analysis of public human tumor RNA-sequencing data (TCGA)
• Who was studied: 8 to 10-week-old C57BL/6 mice injected in the pleural space with AE17 mouse mesothelioma cells, and Balb/c mice injected with AB1 cells (5 × 10 to the 5th cells), studied in groups of about 5 to 10 per experiment; plus RNA-seq data from 88 human mesothelioma tumor samples from the TCGA biobank
• Exposure: No asbestos exposure was studied. The treatments were the CSF1R inhibitor BLZ945 (200 mg/kg by mouth once daily from day 4) and an anti-mouse PDL1 antibody (200 µg into the abdomen every 3 days from day 5), alone or combined, compared with vehicle.
• Main results:
  • In mesothelioma-bearing mice, the CSF1R inhibitor significantly reduced tumor burden and pleural fluid compared with vehicle. It also reduced tumor cell proliferation, increased tumor cell death (apoptosis) and lowered tumor vessel density.
  • In cell culture, neither CSF1 nor the inhibitor affected survival of the mesothelioma cells. The authors therefore attributed the drug's effects to the tumor environment rather than to the tumor cells.
  • Treated mice had a large reduction in tumor macrophages. Myeloid-derived suppressor cells were also significantly reduced.
  • CD8 T cell infiltration of tumors and CD8 activation increased in treated mice. Regulatory T cells were reduced in mice with AE17 tumors but not in mice with AB1 tumors.
  • After CSF1R blockade, PDL1 rose significantly on mesothelioma tumor cells. The authors described this as a compensatory response.
  • In mice, combining the CSF1R inhibitor with anti-PDL1 was more potent against tumor growth and pleural fluid than either treatment alone.
  • In the 88 human mesothelioma tumor samples, CSF1R gene expression was not associated with survival.
  • In human tumors with low CSF1R expression, higher CD8 levels were linked with better prognosis. In tumors with high CSF1R expression, CD8 levels had no impact on survival.
• The authors' conclusion: The authors concluded that CSF1R blockade impaired mouse mesothelioma growth, that it caused a compensatory rise in the PD-1/PDL1 pathway, and that combining it with anti-PDL1 was more effective than either treatment alone. They called for clinical testing of this approach.
• Limitations the authors state:
  • The authors stated that the human tumor data observations do not permit definite conclusions.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Immunotherapy, Macrophage.

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