Explaining Y T cells stop working

Communicating oncology research

Keith S. Taber

…to the best of my knowledge, there is absolutely no reason to suspect that Prof. Theodorescu falsified his academic credentials…

The following text is an extract from a podcast item reporting recently published research into bladder cancer:

"The Y-negative cells cause an immune evasive environment in the tumour, and that, if you will, paralyses, the T cells, and exhausts them, makes them tired and ineffective, and this prevents the Y-negative tumour from being rejected, therefore allowing it to grow much better."

"Exhausted T cells have lost their ability to kill cancer cells, and have lots of proteins on their surface known as checkpoints, which put the brakes on immune responses.

But this exhausting environment made by the tumours could actually be their undoing"

"What they also did, inadvertently I'm sure, is made themselves a lot more vulnerable to one of the most useful and prevalent therapeutics in cancer today, which is immune checkpoint inhibitors."

"Immune checkpoint inhibitors are a class of drugs that block those checkpoint proteins that sit on the surface of T cells, effectively taking the brakes off immune responses, causing T cells to become more aggressive."

Dan Theodorescu & Nick Petrić Howe speaking on the Nature Podcast

Prof. Dan Theodorescu MD, PhD, is the Director of the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai, Professor of Surgery, Pathology and Laboratory Medicine; and corresponding author on the paper (Abdel-Hafiz et al., 2023) published in Nature, and discussed in the podcast.

Nick Petrić Howe, Senior Multimedia Editor at Nature Research, was the journalist presenting the item on the podcast.

Communicating science

Scientific research is communicated to other specialist scientists through research reports which reflect a particular genre of writing, and are written with specialist researchers in the same field as the main target readership. Such reports are usually of a quite technical nature, and (appropriately) assume that readers will have a high level of prior understanding of concepts in the field and the technical language used. Such tropes as simile and analogy certainly can sometimes feature, but generally figurative language is kept to a minimum.

Communication to a wider audience of people with a general interest in science needs to adopt a different register. As I have noted on this site before, this is quite challenging as a general public audience is likely to be very diverse in terms of its level of knowledge and understanding of background to any scientific research. Perhaps that is why as a former teacher (and so a science communicator that could make reasonably informed assumptions about the background of my audience in any particular lesson) I find the language of this type of science dissemination fascinating.

Read about science in public discourse and the media

The gist

The study discussed in the podcast reported on a line of research exploring the genomics of bladder cancer, and in particular how tumours that develop from cells that have deficiencies in the Y chromosome seem to have particular characteristics.

Put simply, tumours of this kind were likely to be inherently more damaging to the patient, although also likely to be more responsive to an existing class of medicines. (At this stage the work has largely relied on in vitro studies and 'animal models' (mice) so the implications for actual human cancer patients are reasonable, but speculative.)

The language used

The short extract of the dialogue I have transcribed above seems quite 'dense' in interesting language when de-constructed:

Y-negative cells – a new technical term?

The extract starts with reference to Y-negative cells. Earlier in the item it had been explained that some cells have no Y chromosome, or an incomplete Y chromosome. (For someone to understand this information, they would need to have some background knowledge relating to what chromosomes are, and why they are important in cells. 1 ) The term Y-negative cell therefore, given that context, refers to a cell which lacks the usual Y chromosome. 2 If such a cell turns cancerous it will give rise to a tumour which is Y-negative (as all the tumour cells are formed from the division of that cancerous cell). The published report notes "Loss of the Y chromosome (LOY) is observed in multiple cancer types, including 10-40% of bladder cancers" (Abdel-Hafiz et al., 2023), an observation which motivates the area of research.

An immune evasive environment?

The word 'evasion' appears in the title of the paper. To evade something means to avoid it, which might suggest a sense of deliberation. Immune evasion is a recognised issue, as in cancers "interactions between the immune system and the tumour occur through complex events that usually eventually climax either in successful tumour eradication or immune evasion by the tumour" (Vinay et al., 2015): that is, either the immune system destroys the cancer, or the cancer is able to grow due to some mechanism(s) that prevent the immune system killing the tumour cells. The 'immune evasive environment' then refers to the environment of the tumour's cells in a context where aspects of the normal immune mechanisms are inoperative or restricted.

Paralysed, exhausted and tired T cells

T cells are one of the classes of cell that make up the immune system, and the item was suggesting that with 'LOY' the T cells are unable to function in the way they normally do when interacting with cancer cells that have an intact Y chromosome. ('LOY' is the acronym for a process, viz., "loss of the Y chromosome", but once defined can be used in a way that reifies LOY as if it refers to an object. 3 In "…with 'LOY'…", I am treating LOY as a medically diagnosable condition.)

Are the T cells paralysed? That normally means not able to move, which is not the case here. So 'paralysed' seems to be used as a metaphor, a way of 'making the unfamiliar familiar' for a non specialist audience. A large part of the task of a science teacher is to make the unfamiliar [become] familiar to learners.

Read about making the unfamiliar familiar

Actually, I would better class this specific use as a simile rather than a metaphor:

"The Y-negative cells cause an immune evasive environment in the tumour, and that, if you will, paralyses, the T cells"

A simile in poetic language normally refers to something being 'like' or 'as' something else, as when the star Betelgeuse was said to be "like an imbalanced washing machine tub" or a laser was described as being used as a "kind of spark plug". Here, Prof. Theodorescu marks the term 'paralyses' with 'if you will' in a similar way to how when selection theory has been said to be "like a Tibetan prayer-wheel…" the word 'like' marks that this is noting a similarity, not an identity (selection theory is not suggested to be a prayer-wheel, but rather to be in some way like one).

Read examples of similes used in discussing science

The T cells were said to be as if paralysed, but they were also exhausted and tired. Yet, again, 'exhausted' does not seem to be meant literally. The T cell has not used up its supply of something (energy, or anything else), so this is another metaphor. 'Tired' can be seen as synonymous to exhausted, except usually 'tired' refers to a subjective experience. The T cells are not sentient and presumably do not feel tired – so, this is another metaphor; indeed an anthropomorphic metaphor, as it refers to the cells as though they have subjective experience like a person.

Read examples of metaphors used in discussing science

Hey, you immune cells – are you feeling tired? How about taking a break, and doing some stretching exercises and a little yoga?

Images from Pixabay

Anthropomorphism is a common trope in science discourse, especially in biological contexts. It can sometimes help communication of abstract material to present scientific phenomena in a narrative that relates to human subjective experience – perhaps referring to disease 'evading' the immune system – but consequently often gets adopted into in students' pseudo-explanations (e.g., the reaction happened because the atom wanted another electron, the gas expands because the molecules wanted more space). 4

Read about types of pseudo-explanations

Read examples of anthropomorphism in science discourse

Yet the term 'exhausted' also appears in the published research report ("Ylow bladder cancers contained a higher proportion of exhausted and progenitor exhausted CD8+ T cells..."). So, this is a term that is being adopted into the terminology of the research field. A paper from 2019 set out to define what this means: "'T cell exhaustion' is a broad term that has been used to describe the response of T cells to chronic antigen stimulation, first in the setting of chronic viral infection but more recently in response to tumours" (Blank, et al., 2019). Another study notes that

"It is now clear that T cells are not necessarily physically deleted under conditions of antigen persistence but can instead become functionally inept and incapable of elaborating the usual array of effector activities typically associated with robust, protective, effector and memory T-cell populations."

Yi, Cox, & Zajac, 2010

It is not unusual for terms that seem to be initially used metaphorically, to become adopted in a scientific field as technical terms (such as the 'birth' and 'death' of stars in astronomy). Indeed, inept seem to me a term that is normally applied to people who have agency and can learn skills, but lack skill in an area where the are active. The field of oncology seems to have adopted the notion of ineptitude, to label some T cells as 'inept'.

Unlike in human hereditary, where we would not assume a child can directly inherit a lack of skill in some area of activity from its parents (there is no gene for playing chess, or spraying cars, or heart surgery, or balancing account books), at the cellular level it is possible to have "inept T-cell lineages" (Fredholm et al, 2018). If one is going to anthropomorphise cells, then perhaps 'inept' is an unfair descriptor for structural changes that modify functionality, and can be passed on to 'daughter' cells: should these cells be considered to have a disability rather than be inept? For that matter, an exhausted T-cell seems to have more in common with a metamorphosed caterpillar than an exhausted marathon runner.

Rejection – a dead metaphor?

'Rejection' is a technical terms used in medical science for when the immune system 'attacks' something that it 'identifies' as not self: be that a tumour or a transplanted tissue. Note that here terms such as 'attacks' and 'identifies' are really also anthropomorphic metaphors to label complex processes and mechanisms that we gloss in human terms.

What actually happens is in effect some chemistry – there is nothing deliberate about what the cancer cells or the immune cells are doing. Tumours that grow quickly are described as 'aggressive' ("…causing T cells to become more aggressive") another term that might be understood as an anthropomorphic metaphor, as aggression normally refers to an attitude adopted. The tumour cells are just cells that grow and divide: they have no attitude nor intentions, and do not deliberately harm their host or even deliberately divide to grow the cancer.

When the term 'rejection' was first suggested for use in these contexts it will have been a metaphor itself, a word transplanted [sic] from one context where it was widely used to another novel context. However, the 'transplant took' (rather than being 'rejected'!) and came to be accepted as having a new biological meaning. Such a term is sometimes called a dead metaphor (or a clichéd metaphor) as it has lost its metaphorical status, and become a technical term. Tumours are now literally rejected. And T cells do now become exhausted (and inept). And tumours can now be aggressive.

Within the specialist field, such words now have nuanced technical meanings, related to, but subtly different from, their source words' usage in general language. Experts know that – but lay people may not always realise. Strictly, the words aggressive in 'an aggressive drunk' and 'an aggressive tumour' are homonyms.

Seated checkpoints: quo vardis, friend or foe?

The same is the case with 'checkpoints'. Referring to proteins on the immune cell surface that interact with proteins on tumour cells, the label 'checkpoints' will have been a metaphorical transplant of an existing term (as in border checkpoints, where it is checked that someone's papers are in order for entry to a country); but, now, this is accepted usage.

T cells are able to destroy other cells. However, they have proteins on their surfaces which can bind to proteins on other cells, and when these are bound the T cells do not destroy the other cells. (Do these proteins really "sit on the surface of T cells" – or is sitting an action only available to organisms with certain types of anatomic features – such as buttocks and jointed legs perhaps? So, this is another metaphor, but one that conveys meaning so readily that most listeners will not have noticed it. 6 )

So, immune cells have evolved because they 'protect' the organism from 'foreign' cells, and the checkpoints have evolved because they prevent the immune cells destroying cells from the same individual organism. 5 This works to the extent that the binding of the checkpoints is specific. Tumour cells (which are derived from the individual) can sometimes bind, and so the T cells may be ineffective in destroying them. Immune checkpoint inhibitors can interfere with the mechanism by which tumour cells act on the T cells as 'self' cells – something sometimes referred to as a checkpoint 'blockade' (yet another metaphor) – something represented in the following image:

Figure entitled "Immune checkpoint blockade for T-cell activation" (note the 'exhausted' T cells) (Fig. 2, from Darvin, et al., 2018. Open access under http://creativecommons.org/licenses/by/4.0/). [There is an interesting mix of iconic (cell shapes) and symbolic (e.g., lightning strikes?) signs in the figure.]

The extract of dialogue quoted above suggests that the checkpoints "put the brakes on immune responses". There are of course no actual brakes, so this is again metaphorical. However, we might consider 'putting the brakes' on as having become an English idiom, that is, the term is now widely understood as applying to any situation where a process is brought to a stop, regardless of whether or not there are actual brakes involved. A raise in bank interest rates might be said to be intended to put the brakes on inflation. (Indeed, as my O level economics teacher at North Romford Comp. habitually explained managing the economy in terms of driving a car – which of course we were all too young to legally have experienced – he may well have actually said this.)

Can tumours behave advertently?

At one point Prof. Theodorescu, suggested that "what [the tumours] also did, inadvertently I'm sure, is made themselves a lot more vulnerable to one of the most useful and prevalent therapeutics in cancer today". I am also sure that this effect was inadvertent. Otherwise, the tumour acted advertently, which would mean it behaved deliberately with this outcome in mind.

It clearly would not seem to be in a tumour's interest to make itself more susceptible to therapeutics, but then agents do sometimes behave in ways that seem irrational to others – for example, because of bravado. So, I do not rule out apparently self-destructive behaviour from being deliberate (as I drafted this piece, the news broadcast reports on an apparent coup attempt in Russia, suggesting that a few tens of thousands of men are looking to take over a nation of over 140 million that had been paying them to fight in the illegal invasion of Ukraine). Rather, my reason for being sure this not deliberate, is that I do not think that a tumour is the kind of entity that can behave advertently. 7

So, I do not disagree with Prof. Theodorescu, but I do think that stating that, in this case, the behaviour was inadvertent seems to imply that that a tumour can in some circumstances act deliberately (i.e., anthropomorphism, again). I am sure that was not the intention, but it seems, inadvertently I'm sure, to reflect the tactic of conspicuously stating someone is not guilty of some act as a means of starting a contrary rumour.

So, I would like to make it absolutely clear, without any sense of ambiguity, that, certainly to the very best of my knowledge, there is absolutely no reason to suspect that Prof. Theodorescu falsified his academic credentials using red crayons and recycled cereal packets.

Work cited:
Notes:

1 Any communication of science will inevitably have to assume some background. In teaching, we can use conceptual analysis to break down any topic and identify pre-requisite prior knowledge that will be needed before introducing new information. Science education builds up understanding slowly over many years, 'building on' what learners have already been taught. Anyone asked to give an account or explanation to a general audience has to make an informed judgement of where it is reasonable to start.

2 It might seem that the cells of females are 'Y-negative' as these do not usually contain Y chromosomes. However, from the context (the discussion of loss of, or incomplete, Y-chromosomes) the term is being used to refer to cells with no Y chromosomes that derived ultimately (by imperfect copying) from a cell which did have a Y chromosome. That is, this is a feature of tumours in men.

Although women do not (usually) have Y chromosomes, it is sometimes suggested that the man's Y chromosome can be considered an incomplete X chromosome, so in a sense all men might be considered as incomplete, imperfect women, as some readers might have long suspected.

3 This is not meant as some kind of criticism, but rather an observation on one of the affordances of language in use. It is very useful for the scientist to package up an idea (here, the loss of the Y chromosome from a cell's set of nuclear chromosomes) in a new term or acronym, which can then be put to work as a neologism, thus simplifying sentence structure. The reader then needs to decode this new term in various contexts. That is perfectly reasonable within the genre of research reports (as this only adds minimally to the interpretative load of a specialist reader who is likely to have strong enough background to have capacity to readily make sense of the new term in various contexts). So, in the published paper (Abdel-Hafiz, 2023), we find, inter alia,

  • "…LOY correlates with…"
  • "…naturally occurring LOY mutant bladder cancer cells…"
  • "In ageing men, LOY has been associated with many adverse health consequences."
  • "…cancer cells with LOY…"
  • "…mouse tumours with LOY…"
  • "…human bladder cancer specimens with LOY…"
  • "…LOY is present early in disease progression…"
  • "…the lack of Y chromosome gene expression in the MB49 sublines was due to LOY"
  • "…the important role of these two genes in conferring the LOY phenotype…"
  • "…patients with LOY had a reduced overall survival following surgery…"
  • "…tumours with LOY grew more aggressively…"
  • "…the mechanism of LOY-driven tumour evasion…"

There is even a case of LOY being taken as a sufficiently familiar to be compounded into a further acronym, 'MADLOY':

"we used TCGA DNA sequencing data and mosaic alteration detection for LOY (MADLOY) to detect LOY".

4 Unfortunately, thinking anthropomorphically about viruses, cells, molecules, etc., can become a habit of mind. Students may come to see such anthropomorphisms as having the status of genuine scientific explanations (that they can use in exams, for example). Therefore, care is needed with using anthropomorphism in science teaching (Taber & Watts, 1996).

Read about anthropomorphism and science learning

5 So, we might suggest that

  • 'checkpoints' is a recently deceased metaphor, with its new meaning only familiar in the technical language community of oncologists and cognate specialists, whereas
  • 'sits' is a long dead metaphor as its broader meaning is likely to be understood widely within the natural language community of English speakers.

6 My use of 'because' is not to be read in a teleological sense as

  • immune cells have evolved in order to protect the organism from 'foreign' cells
  • the checkpoints have evolved in order to prevent the immune cells destroying cells form the same individual organism

Rather in the sense of the reason something has evolved is because it has a property that offers an advantage, and so was selected for:

  • immune cells have evolved because they were selected for because they protect the organism from 'foreign' cells
  • the checkpoints have evolved because they were selected for because they prevent the immune cells destroying cells from the same individual organism

7 I am making an 'ontological judgement'. I might say I am doing ontology. In my teaching of graduate students I found some were wary of terms like ontology and epistemology, but actually I would argue that we all 'do ontology' every time we make a judgement about the kind of entity something is (and we do epistemology every time we make a judgement about the likely truth value of some claim).

If you judge that fairies are imaginary or that dinosaurs are extinct, I suggest that you are doing ontology. For that matter, if you judge that fairies and dinosaurs are alive and well, and live at the bottom of your garden, then you are also doing ontology – if perhaps not so well.

Read about ontology

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Author: Keith

Former school and college science teacher, teacher educator, research supervisor, and research methods lecturer. Emeritus Professor of Science Education at the University of Cambridge.

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