Rapid activation of tumor-associated macrophages boosts preexisting tumor immunity

Our plain-English summary of Rapid activation of tumor-associated macrophages boosts preexisting tumor immunity, by S. Hoves, C.H. Ooi, C. Wolter, et al (The Journal of Experimental Medicine, 2018).

The study

• Authors: S. Hoves, C.H. Ooi, C. Wolter, H. Sade, S. Bissinger, M. Schmittnaegel, O. Ast, A.M. Giusti, K. Wartha, V. Runza, W. Xu, Y. Kienast, M.A. Cannarile, H. Levitsky, S. Romagnoli, M. De Palma, D. Rüttinger, C.H. Ries
• Journal: The Journal of Experimental Medicine
• Published: 2018;215(3):859-876
• Cited by: 179 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Depletion of immunosuppressive tumor-associated macrophages (TAMs) or reprogramming toward a proinflammatory activation state represent different strategies to therapeutically target this abundant myeloid population. In this study, we report that inhibition of colony-stimulating factor-1 receptor (CSF-1R) signaling sensitizes TAMs to profound and rapid reprogramming in the presence of a CD40 agonist before their depletion. Despite the short-lived nature of macrophage hyperactivation, combined CSF-1R+CD40 stimulation of macrophages is sufficient to create a proinflammatory tumor milieu that reinvigorates an effective T cell response in transplanted tumors that are either responsive or insensitive to immune checkpoint blockade. The central role of macrophages in regulating preexisting immunity is substantiated by depletion experiments, transcriptome analysis of ex vivo sorted TAMs, and gene expression profiling of whole tumor lysates at an early treatment time point. This approach enabled the identification of specific combination-induced changes among the pleiotropic activation spectrum of the CD40 agonist. In patients, CD40 expression on human TAMs was detected in mesothelioma and colorectal adenocarcinoma.

© 2018 Roche Diagnostics GmbH.

In plain English

This was a laboratory study in mice combined with staining of human tumour tissue. Mice with transplanted MC38 adenocarcinoma, E0771 breast and T241 tumours received an anti-CSF-1R antibody, an agonistic anti-CD40 antibody, both, or control antibodies. In MC38 tumours, the combination gave greater antitumour responses than either antibody alone: when treatment started at about 80 mm3, 2/10 mice showed complete regression, and when it started at about 200 mm3, 6/10 were tumour free. Summarising experiments that started treatment at tumour volumes above 100 mm3, the article reports that 47/70 combination-treated animals, which it gives as 68%, were tumour free. E0771 and T241 tumours also responded better to the combination than to either antibody alone, but with lower response rates than MC38. In MC38 mice, depleting macrophages beforehand abolished the effect, while isotype-pretreated mice had tumour rejection in 7/10. Depleting CD8+ T cells abolished the survival benefit; depleting CD4+ T cells or NK cells did not. Gene and protein analyses 16 h after dosing showed a proinflammatory macrophage profile. In tissue from 9 colorectal cancer and 19 mesothelioma patients, CD40 was found on tumour-associated macrophages, with greater between-patient variability in mesothelioma. The study did not examine asbestos exposure.

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: Preclinical experimental study in mouse tumour models, with immunohistochemistry of human tumour tissue
• Who was studied: Mice bearing transplanted MC38, MC38-OVA, E0771, T241 or CT26.WT tumours (generally 10 mice per treatment group); human tumour tissue from 9 colorectal cancer and 19 mesothelioma patients
• Exposure: Antibody treatments: anti-CSF-1R (clone 2G2, 30 mg/kg, weekly) and agonistic anti-CD40 (rat IgG2a clone FGK.45, 4 mg/kg, once), alone or combined; comparison treatments included anti-PD-1 and anti-CTLA-4
• Main results:
  • In MC38 tumour-bearing mice given the combination, 2/10 showed complete regression when treatment began at small tumour size (about 80 mm3), and 6/10 were tumour free when treatment began at larger tumour size (about 200 mm3)
  • Pooled across experiments run under similar conditions, with tumour volume above 100 mm3 at the start of treatment, 47/70 combination-treated animals were tumour free, which the article states as 68%
  • In the E0771 and T241 models the combination improved antitumour activity compared with single agents, but with lower response rates than in MC38
  • In MC38 tumour-bearing mice, removing macrophages before therapy abolished the combination's antitumour effect, while isotype-pretreated mice had tumour rejection in 7/10
  • In MC38 tumour-bearing mice, CD8+ T cell depletion removed the survival benefit of the combination; CD4+ T cell and NK cell depletion did not
  • In the large MC38 tumours, anti-PD-1 alone or with anti-CTLA-4 did not improve survival
  • In human colorectal adenocarcinoma and mesothelioma samples, CD40+ TAM density correlated positively with CD163+ and CSF-1R+ TAM density
  • Between-patient variation in CD40+ TAM density was greater in mesothelioma than in colorectal cancer samples
  • In mice, adding anti-CSF-1R to anti-CD40 produced no additional microscopic liver toxicity compared with anti-CD40 alone
• The authors' conclusion: The authors concluded that their findings describe a mechanism by which tumor-associated macrophages are redirected against the tumour, now being translated to the clinic to evaluate whether dual CSF-1R plus CD40 targeting drives antitumour immunity in patients as well as in mice
• Limitations the authors state:
  • The authors state that which myeloid populations respond to the combination remains unclear and would require further kinetic transcriptome analysis
  • The authors state that intermittent dosing schedules could not be tested in mice because of anti-drug antibody formation against the rat anti-mouse CD40 antibody
  • The authors state that effects on vessel integrity from perivascular macrophage depletion plus CD40 agonism cannot be excluded

Topics

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

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• Pathogenesis of mesothelial reactions to asbestos fibers. Monocyte recruitment and macrophage activation — R.M. Branchaud, L.J. Garant, et al. (1993)
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