Depletion of Tumor-Associated Macrophages with a CSF-1R Kinase Inhibitor Enhances Antitumor Immunity and Survival Induced by DC Immunotherapy

Our plain-English summary of Depletion of Tumor-Associated Macrophages with a CSF-1R Kinase Inhibitor Enhances Antitumor Immunity and Survival Induced by DC Immunotherapy, by F. Dammeijer, L.A. Lievense, M.E. Kaijen-Lambers, et al (Cancer Immunology Research, 2017).

The study

• Authors: F. Dammeijer, L.A. Lievense, M.E. Kaijen-Lambers, M. van Nimwegen, K. Bezemer, J.P. Hegmans, T. van Hall, R.W. Hendriks, J.G. Aerts
• Journal: Cancer Immunology Research
• Published: 2017;5(7):535-546
• Cited by: 128 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

New immunotherapeutic strategies are needed to induce effective antitumor immunity in all cancer patients. Malignant mesothelioma is characterized by a poor prognosis and resistance to conventional therapies. Infiltration of tumor-associated macrophages (TAM) is prominent in mesothelioma and is linked to immune suppression, angiogenesis, and tumor aggressiveness. Therefore, TAM depletion could potentially reactivate antitumor immunity. We show that M-CSFR inhibition using the CSF-1R kinase inhibitor PLX3397 (pexidartinib) effectively reduced numbers of TAMs, circulating nonclassical monocytes, as well as amount of neoangiogenesis and ascites in mesothelioma mouse models, but did not improve survival. When combined with dendritic cell vaccination, survival was synergistically enhanced with a concomitant decrease in TAMs and an increase in CD8+ T-cell numbers and functionality. Total as well as tumor antigen-specific CD8+ T cells in tumor tissue of mice treated with combination therapy showed reduced surface expression of the programmed cell death protein-1 (PD-1), a phenomenon associated with T-cell exhaustion. Finally, mice treated with combination therapy were protected from tumor rechallenge and displayed superior T-cell memory responses. We report that decreasing local TAM-mediated immune suppression without immune activation does not improve survival. However, combination of TAM-mediated immune suppression with dendritic cell immunotherapy generates robust and durable antitumor immunity. These findings provide insights into the interaction between immunotherapy-induced antitumor T cells and TAMs and offer a therapeutic strategy for mesothelioma treatment. Cancer Immunol Res; 5(7); 535-46. ©2017 AACR.

©2017 American Association for Cancer Research.

In plain English

This was a laboratory study in mice, not people. The authors injected mesothelioma cells into the abdomens of female BALB/c and CBA/J mice. The two cell lines (AB1 and AC29) came from mouse tumors originally induced by injected crocidolite asbestos. The mice received one of four treatments: PLX3397 (pexidartinib), a drug given in their food that targets tumor-associated macrophages (a type of immune cell); a dendritic cell vaccine; both; or neither. In CBA/J mice, the drug alone reduced these macrophages, tumor blood vessels and ascites (abdominal fluid), but it did not improve survival in either model. The vaccine alone prolonged survival only in the AC29 model, while the combination improved survival in both. In combination-treated mice, CD8+ T cells in the tumor showed fewer signs of exhaustion. Surviving CBA/J mice that had received the vaccine, with or without the drug, stayed disease free when injected with tumor cells again. All tumor-naive comparison mice reached their humane endpoint. The authors concluded that the drug alone has limited effect in mesothelioma, but that combined with the vaccine it produced durable tumor responses.

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 in two mouse mesothelioma models, using cell lines that came from mouse tumors originally induced by crocidolite asbestos
• Who was studied: Female 8-12 week old BALB/c mice (6 per treatment arm, AB1 cells) and CBA/J mice (8 per treatment arm, AC29 cells), housed at Erasmus MC, Rotterdam, The Netherlands
• Exposure: Not an asbestos exposure study. The treatments tested were the CSF-1R kinase inhibitor PLX3397 given in chow (290 mg per kg of chow, about 45 mg/kg per day), tumor lysate-pulsed dendritic cell vaccination given into the abdomen on day 10, or both
• Main results:
  • PLX3397 alone did not improve survival in either mouse model
  • Dendritic cell therapy alone prolonged survival only in the AC29 (CBA/J) model
  • The combination of PLX3397 and dendritic cell therapy improved survival in both models
  • In CBA/J mice, PLX3397 reduced F4/80+ macrophages, CD31+ endothelial (blood vessel) cells and CD206+ (M2) cells in tumors compared with control mice
  • PLX3397-treated CBA/J mice had less ascites
  • Depleting macrophages alone did not increase the CD8+ T cells already present in the tumors
  • In the blood, PLX3397 nearly eliminated nonclassical monocytes, from about 40 to 5-10 cells per microliter
  • When dendritic cell therapy was combined with macrophage depletion, a smaller proportion of tumor CD8+ T cells had the high PD-1 levels linked to T-cell exhaustion
  • When re-injected with tumor cells, surviving CBA/J mice treated with dendritic cell therapy alone or in combination remained disease free, while all tumor-naive mice reached their humane endpoint
  • After rechallenge, T-cell proliferation was higher in combination-treated mice than in mice given dendritic cell therapy only
• The authors' conclusion: The authors concluded that macrophage-depleting treatment alone has limited effect in mesothelioma, but that combined with a dendritic cell vaccine it can produce durable tumor responses and functional antitumor immunity
• Limitations the authors state:
  • Only a limited number of mice were available for the blood analyses in the AB1 (BALB/c) model
  • The authors did not determine which property of the macrophages drives T-cell exhaustion
  • The origin of tumor-associated macrophages remains uncertain

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

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

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