Trained innate immunity attenuates macrophage efferocytosis of cancer cells
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Curated by eLife
eLife Assessment
This study provides proof-of-principle data for the use of trained immunity to modulate macrophage interactions with tumours. The study makes a valuable contribution to the field of trained immunity. However, the study is incomplete without vivo data, which would have made the claims in the paper stronger by providing meaningful context for the in vitro experiments that were conducted.
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Abstract
Macrophage phagocytosis has been implicated in regulating anti-tumour immunity. Trained innate immunity (TII), induced via modulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Despite the advances in the study of TII-mediated anti-tumour activity, the impact of TII on the orchestration of phagocytosis in the tumour setting requires further elucidation. Here, we investigated whether macrophage phagocytosis of tumour cells can be modulated through induction of TII.To this end, mice were pre-treated with β-glucan, a fungal-derived agonist of TII, and bone marrow was isolated for macrophage differentiation. Macrophages were then co-cultured with tumour cells that were either apoptotic or opsonised with an antibody recognising a tumour antigen, to mimic efferocytosis and antibody-dependent cellular phagocytosis (ADCP), respectively.While TII did not have any impact in the modulation of ADCP, efferocytosis was decreased in trained macrophages. Along the same line, gene expression analysis demonstrated that mRNA levels of molecules promoting efferocytosis were downregulated in trained macrophages. Trained macrophages exerted decreased levels of active caspase-1 and produced decreased levels of interleukin-1β upon efferocytosis of tumour cells.Our findings reveal a hitherto unknown role of TII in the regulation of anti-tumour immunity and may set the stage for designing new cancer immunotherapeutic approaches targeting macrophage efferocytosis.
Article activity feed
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eLife Assessment
This study provides proof-of-principle data for the use of trained immunity to modulate macrophage interactions with tumours. The study makes a valuable contribution to the field of trained immunity. However, the study is incomplete without vivo data, which would have made the claims in the paper stronger by providing meaningful context for the in vitro experiments that were conducted.
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Reviewer #1 (Public review):
Summary:
The authors were attempting to describe whether trained innate immunity would modulate antibody-dependent cellular phagocytosis (ADCP) and/or efferocytosis.
Strengths:
The use of primary murine macrophages, and not a cell line, is considered a strength.
The trained immunity-mediated changes to phagocytosis affected both melanoma and breast cancer cells. The broad effect is consistent with trained immunity.
Weaknesses:
The most significant weakness, also noted by the authors in the discussion, is the lack of in vivo data. Without these data, it is not possible to put the in vitro data in context. It is unknown if the described effects on efferocytosis will be relevant to the in vivo progression of cancer.
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Reviewer #2 (Public review):
Summary:
The authors follow up their preclinical work on beta-glucan-induced trained immunity in murine tumor models that they published in Cell in 2020. In particular, they focus on the role of trained immunity and efferocytosis of cancer cells
Strengths:
While properly conducted, the work is underwhelming and fully depends on in vitro observations performed with co-cultures of bone marrow derived macrophages from beta-glucan-treated mice and tumor cell lines. From these in vitro studies, the authors conclude that trained immunity induction has no effect on antibody-dependent cellular phagocytosis, while it decreases efferocytosis.
Weaknesses:
It would be important to study these phenomena in tumor mouse models in vivo. The authors clearly have the expertise as they have shown in previous studies. …
Reviewer #2 (Public review):
Summary:
The authors follow up their preclinical work on beta-glucan-induced trained immunity in murine tumor models that they published in Cell in 2020. In particular, they focus on the role of trained immunity and efferocytosis of cancer cells
Strengths:
While properly conducted, the work is underwhelming and fully depends on in vitro observations performed with co-cultures of bone marrow derived macrophages from beta-glucan-treated mice and tumor cell lines. From these in vitro studies, the authors conclude that trained immunity induction has no effect on antibody-dependent cellular phagocytosis, while it decreases efferocytosis.
Weaknesses:
It would be important to study these phenomena in tumor mouse models in vivo. The authors clearly have the expertise as they have shown in previous studies. Especially because the in vitro observation appears to conflict with the in vivo anti-tumor found in mice prophylactically treated with beta-glucan. Clearly, trained immunity is associated with diverse cellular responses and mechanisms, some of which may promote tumor growth, as the current manuscript suggests, but in the absence of in vivo studies, it is merely a mechanistic exercise of which the relevance is difficult to determine.
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Reviewer #3 (Public review):
Summary:
Chatzis et al showed that β-glucan trained macrophages have decreased phagocytic activity of apoptotic tumor cells and that is accompanied by lower levels of secreted IL-1β using a mouse model.
Strengths:
This finding has a potential impact on designing new cancer immunotherapeutic approaches by targeting macrophage efferocytosis.
Weaknesses:
Whether this finding could be applied to other scenarios is underdetermined.
(1) Does the decrease of efferocytosis also occur in human monocytes/macrophages after training?
(2) Both β-glucan and BCG are well-trained innate immunity agents, the authors showed that β-glucan decreased efferocytosis via IL-1 β, so it is interesting to know whether BCG has a similar effect.
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