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π Health and biotech
Tumours: “better understanding has improved treatments”

Cancer immunotherapies: how do they work?

Agnès Vernet, Science journalist
On October 21st, 2021 |
3 mins reading time
2
Cancer immunotherapies: how do they work?
Julien Husson
Julien Husson
Professor at École Polytechnique in the Hydrodynamics Laboratory (LadHyX *)
Key takeaways
  • Tumours weaken the immune response in patients and immunotherapies – drugs to ‘wake up’ the immune system – have proven effective.
  • Whilst these treatments are shown to work on the clinical level, their exact mechanism of action if not fully understood.
  • As such, biophysicist Julien Husson is trying to understand how immunotherapies block the immunosuppressive effect of tumours, using electron microscope analysis.
  • In future work, he hopes to use the findings to better understand the mechanism behind how T lymphocytes (immune cells) work.

If can­cers man­age to devel­op in a patient, it is because of the abil­i­ty of tumours to both grow quick­ly and to manip­u­late the immune sys­tem. Tumours can weak­en the immune response and, as such, drugs tar­get­ing and ‘wak­ing up’ the immune sys­tem – such as the immunother­a­pies known as anti-CTLA4, anti-PD1 and anti-PDL1 – have rapid­ly become treat­ments of choice for can­cer patients1. Their effec­tive­ness has result­ed in more long-term remis­sions than before and, while great progress in can­cer treat­ments have been made thanks to advances in biol­o­gy, the oppo­site is also true. To bet­ter under­stand how this works, find­ings from clin­i­cal research into immunother­a­pies is help­ing sci­en­tists in fun­da­men­tal research to know where to look.

Waking up the immune system

Bio­physi­cist Julien Hus­son, a researcher at the Lab­o­ra­toire d’hy­dro­dy­namique (Lad­HyX) at the Insti­tut Poly­tech­nique de Paris, is a good exam­ple of this type of work of. “My aim is to mod­el the way in which a tumour cell and the cells of the immune sys­tem inter­act,” he says. Notably, he is try­ing to under­stand a fun­da­men­tal and cru­cial aspect of immunother­a­py; the way the treat­ments man­age to re-awak­en T cells – the cells of the immune sys­tem that are nor­mal­ly sup­pressed by can­cer. In oth­er words he is try­ing to under­stand, “how immunother­a­pies block the immuno­sup­pres­sive effect of tumours and reac­ti­vate T lymphocytes.”

The key to this inter­ac­tion is known to be an anti­body, PD-L1, found on the sur­face of tumour cells, which binds to T cells that pass close by the tumour. When it comes into con­tact with the PD‑1 recep­tor of these immune cells, it inhibits their activ­i­ty, like a con­trol switch. The T cells are switched off, unable to direct their weapons at the abnor­mal cell. To pre­vent tumours hi-jack­ing patients’ immune cells in this way, immunother­a­pies are designed to block this inhi­bi­tion. As such, patients are giv­en small anti-PD-L1 mol­e­cules, which bind specif­i­cal­ly to the tumour cell’s PD-L1 anti­body and thus pre­vent it from turn­ing off the T cells. This inhi­bi­tion of inhi­bi­tion wakes up the immune sys­tem – or rather pre­vents it from being blocked. But to under­stand more about how this hap­pens, researchers are seek­ing to first under­stand how the tumour anti­body acts on the T cell in detail.

Observing cells closely

To study this effect, Julien Hus­son attached PD-L1 anti­bod­ies onto glass beads as sim­pli­fied mod­els of tumour cells and filmed the reac­tion of an immune cell to it using an elec­tron micro­scope. “We found that when T cells come into con­tact with an anti­body, it pro­duces huge pro­tru­sions,” says Julien Hus­son, who was the first to observe a real ‘kiss’ between a lym­pho­cyte (T cell) and a tumour (you can watch the video below, or here).

“But when this anti­body is PD-L1, the pro­tru­sions become more rigid,” he says. He observes changes in shape these cel­lu­lar pro­tru­sions, their struc­ture appears less mobile under the micro­scope. Julien Hus­son there­fore assumes that, under nor­mal cir­cum­stances, when the tumour and T cell come into con­tact, it results in a remod­el­ling of the cytoskele­ton (the inter­nal struc­ture of the T cell). This pro­found mod­i­fi­ca­tion of the immune cell seems to allow it to mobilise its cyto­tox­ic sys­tem to attack the abnor­mal cell, i.e. the tumour. But when the tumour releas­es PD-L1, the remod­el­ling seems dif­fer­ent and serves to block this immune acti­va­tion; mean­ing the immune cell can­not attack the tumour.

The kiss of the lym­pho­cytes ©Julien Hus­son / LadHyx

To con­firm his hypoth­e­sis, Julien Hus­son is prepar­ing to repro­duce this exper­i­ment by replac­ing the glass beads with cells from real patients thanks to a col­lab­o­ra­tion with Claire Hivros of the Insti­tut Curie. This work could help doc­tors under­stand why some patients do not respond to immunother­a­py. “This exper­i­ment involves extreme­ly pre­cise phys­i­cal manip­u­la­tions and involves work­ing on a real med­ical prob­lem,” explains the researcher from the Insti­tut Poly­tech­nique de Paris. It is part of an increas­ing­ly mul­ti-dis­ci­pli­nary approach that is fuelled by inter­ac­tions between clin­i­cal and fun­da­men­tal research.  “It’s a long chain of events. In a few years’ time, our work could per­haps be used to improve the ther­a­peu­tic strate­gies offered to patients,” explains Julien Hus­son. But ini­tial­ly he hopes to shed light on the func­tion­ing of T lymphocytes.

For more information

Sci­ence Sig­nal­ing, 2020; 13(627), eaaw8214. Dia­cyl­glyc­erol kinase z reg­u­lates actin cytoskele­ton remod­el­ing and mechan­i­cal forces at the B cell immune synapse. Sara V. Meri­no-Cortes, Sofia R. Garde­ta, Sara Roman-Gar­cia, Ana Martínez-Riaño, Judith Pineau, Rosa Liebana, Isabel Meri­da, Ana-Maria Lennon Dume­nil, Pao­lo Pier­obon, Julien Hus­son, Bal­bi­no Alar­con, and Yolan­da R. Carrasco.

1https://www.nature.com/articles/s41568-021–00347‑z