Trained innate immunity attenuates macrophage efferocytosis of cancer cells

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.

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.

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.