New Evidence on Macrophages in Cancer Immunotherapy - [Research Highlights]

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In a recent communication in Nature Reviews Drug Discovery, Villanueva (2017) reviews, in brief, the findings from two 2017 studies that looked into the role of macrophages (specifically, tumor associated macrophages - TAMs) in cancer immunotherapy.

One of the most 'popular' topics in cancer immunotherapy is PD1 inhibition. PD1 is a programmed cell death protein expressed on T cells; it has two ligand, PDL1 and PDL2; PDL1 is expressed in almost all cancer mouse models, while PDL2 only in a few.

In short, what PD1 and its ligands do is to promote self-tolerance and negatively regulate immune response; simplistically put, inhibiting PD1 activates the immune system to attack tumors.

As per Villanueva, there is not much information about the PD1/PDL1 pathway and its effects on the different components of the tumor microenvironment, one of these being TAMs.

"New findings reveal that macrophages are also important when targeting the PD1–PDL1 axis. In one article, Pittet and collaborators show that macrophages can remove anti-PD1 antibodies from T cells, blunting their response, whereas in another paper, Weissman and colleagues demonstrate that macrophages also express PD1 on their surface, which impairs their phagocytic activity." [source]

So, double down on that for tumor progression.

In one study, Pittet and colleagues (2017) analyzed in vivo the tumor microenvironment in mice grafted with colon cancer. They labeled monoclonal antibodies targeting PD1 (alpha-PD1) and followed them:

"Reporter mice with labelled T cells and TAMs showed tagged α-PD1 on T cells as early as 5 minutes after injection with a pericellular distribution. However, α-PD1 was then transferred to neighbouring TAMs within minutes, where it was retained." [source]

In later experiments, they learned that TAMs do not express PD1 and that the antibody is not engulfed via phagocytosis. Rather, the mechanism of action is much more complex; what's not complex about cancer?

In the other study, Weisman and colleagues (2017) started by asking whether TAMs express PD1. Their rationale sprung from previous results showing that upon infection, macrophages express PD1:

"The authors found that 50% of macrophages isolated from tumours derived from the CT26 colon cancer cell line expressed PD1 on the surface — a number that increased with time after engraftment — whereas no circulating monocytes or splenic macrophages had detectable PD1 expression." [source]

Further, the researchers wanted to know the effects of PD1 expression in TAM phagocytosis in mice cancer cells without T cells.

"PD1+TAMs displayed reduced tumour cell phagocytosis compared with PD1-TAMs. Treatment of these mice with mAbs targeting PD1 or PDL1 reduced tumour growth, and these effects were abrogated by TAM depletion, confirming that inhibition of the PD1–PDL1 axis in TAMs is responsible for the observed antitumour response." [source]

Ultimately, they looked at what happens when inhibiting CD47 (an anti-phagocytic protein) in combination with a PDL1-targeting monoclonal antibody and they observed increased reduction in tumors and higher survival.

While not definitory, these studies are revelatory and they add up to our ever growing knowledge on the complexity of cancers. The findings in these two studies, well summarized by Villanueva, allow us to better understand and develop potential strategies in cancer immunotherapy.

I'd recommend reading the communication here and both papers (for the detail oriented):

• Pittet et al. (2017)
• Weismman et al. (2017)

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Cristi Vlad, Self-Experimenter and Author