Outside the box

Comprehending the macrophage swing voter

Whenever the subject of elections comes up on news programmes, and in the last few months it has come up quite a lot, few terms provide as much grist for the pontificating punditry mill as ‘swing voters’.

Who and where these voters are, what they want, how they lean, and who they will finally cast their lot with, and their ballots for, is the source of endless, and sometimes heated commentary on TV.

In simple terms, swing voters are, as the name implies, those whose allegiance is not set in stone, and whose ambivalence makes them, theoretically at least, persuadable.

In a closely contested ‘jump ball’ election with an evenly divided partisan affiliation, more like the one in the US than what occurred in the UK, the swing voters are pivotal players because their votes may decide the outcome.

In this era of binary partisanship, where most of the electorate picks a side, and deifies/demonises candidates according to their political affiliation and Weltanschauung, swing voters are pulled – or pushed – in both directions.

If political ideology describes a spectrum, ranging from strongly conservative (Reform UK/MAGA) to centre right/left (Republicans and Tories/Democrats and Labour) and to strongly liberal (Greens/Progressives), and each side has a highly positive opinion of its candidate and a very negative opinion of the other, then the swing voters occupy the increasingly rarefied middle ground between these two polarised extremes.

They may lean towards one or the other candidate, like them both equally, or dislike or even hate them both equally but, on balance, they tend to be less partisan and more malleable.

It is not hard to see why, then, that political campaigns, consultants and pundits focus so much of their time, money and attention on these swing voters at the margins whose allegiance is fickler, and more ‘up for grabs’ than voters located near the two end points of the spectrum.

And so it is with macrophages who are liable to switch sides in several different disease states like tuberculosis, endometriosis and cancer.

So it is also with pharmaceutical companies that have invested substantial resources to target these ‘persuadable’ macrophages, which are the focus of this article.

Unlike swing voters, macrophages (Greek for ‘big eaters’ because they typically devour foreign materials with their pseudopods, which is Greek for ‘false feet’) are a group of immune cells that tend to polarise at two extremes of a continuous spectrum: between the hard right M1 macrophages and the ultra-liberal M2 macrophages.

On the right end of the spectrum, M1 macrophages are akin to gun-toting, ‘law and order’ hawks since they engulf and digest foreign invaders, secrete inflammatory proteins or cytokines such as IL-12, IL-1β, IL-6, TNF-α and present antigens to T cells for the initiation of adaptive immunity.

On the left side, M2 macrophages are soft on security, anti-inflammatory, immune suppressive, angiogenic ‘peaceniks’ that espouse a ‘live-and-let-live’ tolerance over the uncompromising intolerance of M1 macrophages to foreign pathogens, tumour cells, and damaged and dead cells.

However, like swing voters who switch back and forth between candidates, macrophages can reverse polarisation depending on the context.

Macrophages are the first line of defence against Mycobacterium tuberculosis (Mtb), a human pathogen and the causative agent behind tuberculosis (TB) that infects an estimated 10 billion people and is responsible for 1-2 million deaths annually.

Whether growth conditions for Mtb are propitious or restrictive depends, somewhat simplistically, on the dynamics of macrophage polarisation and the relative frequency of M1 and M2 macrophages. In the presence of pro-inflammatory M1 macrophages, Mtb can be eradicated.

However, anti-inflammatory M2 macrophages, which predominate in tuberculosis patients, serve as a reservoir for Mtb survival, maintenance and persistence.

Mtb has evolved to develop resistance to approved anti-tubercular medications like rifampin, isoniazid, pyrazinamide and ethambutol.

Several repurposed drugs like everolimus for advanced renal cell carcinoma, metformin for type II diabetes and statins for high cholesterol are under investigation in clinical trials on the premise that they may help to ‘flip the script’ on TB through macrophage activation.

The same dynamic is at work in tumours where M2 macrophages, known as tumour-associated macrophages (TAMs), predominate.

These TAMs are like dams because they ‘dam up’ the anti-cancer activity of most therapies including immune checkpoint inhibitors like nivolumab (Opdivo) and pembrolizumab (Keytruda) that are otherwise touted as game changers for multiple malignancies.

The more TAMs that are present, the worse the prognosis because TAMs support cell proliferation, invasion, immune evasion, angiogenesis and metastasis, as shown below.

In that sense, TAMs are also pronounceable as imprecatory ‘damns!’ in the sense that their presence is closely associated with treatment resistance.

A small molecule that I work closely with, RRx-001 (nibrozetone), specifically targets TAMs and converts them from M2-like to M1-like in cancer, endometriosis and other diseases, and, hopefully, in this way, turns bane to boon and treatment resistance to treatment resensitisation.

Unlike the fixed ideological extremism, and hyperpartisan identification that most particularly defines the US electorate, macrophages, like swing voters, are malleable to internal and external developments no matter on what side of the spectrum they currently reside.

It is important to disabuse any mistaken impression that may have arisen that M1 macrophages are ‘all good’ and their M2 counterparts are ‘all bad’ since under physiological conditions both play important and indispensable roles.

M2 macrophages contribute to the resolution of inflammation and repair, the failure of which drives the progression of numerous diseases like heart failure, rheumatoid arthritis, type 2 diabetes, chronic obstructive pulmonary disease (COPD) and Parkinson’s disease, to name a few.

M1 macrophages, on the other hand, act as scavengers that rid the host of microbial, malignant and damaged or dead cells, and any failure to carry out these anti-disease and anti-housekeeping functions is often incompatible with survival.

Hence, a fine balance between M1 and M2 polarisation is needed to maintain organismal stability or homeostasis.

That said, several diseases caused by intracellular bacteria, and parasites such as Mycobacterium tuberculosis, Brucella and Leishmania as well as cancer and endometriosis lesions, depend on and co-opt the laissez faire presence of M2 macrophages to grow and thrive.

Fortunately, these M2 macrophages, unlike the diseased cells they support, are much more ‘swingable’, that is, they may change adaptively in response to intrinsic and extrinsic factors.

The focus of several pharmaceutical companies like the one I work for, EpicentRx, is on how therapeutically to ‘persuade’ these macrophages to switch their affiliation from M2 to M1, empowering them to ‘vote’ against disease. Not with their feet, of course – since they don’t have any – but with their engulfing false feet or pseudopods.

Bryan Oronsky is Chief Medical Officer at EpicentRx. Go to epicentrx.com