1/PD-1 #biology has had a renaissance in recent years

#Immunology

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🧵" title="Thread" aria-label="Emoji: Thread">

Schematic from "A Cure Within" ISBN 1621822176 p.33
2/Let me get back in history for one tweet.

Basically, PD-1 KO mice do not have the dramatic proinflammatory lethal phenotype of CTLA-4 KO

So it was hard to predict that this molecule has any future as a therapeutic intervention, let alone a bigger promise than CTLA-4
3/ What& #39;s the mechanism?

It remained complicated for a while (and remains so in my opinion)

For example, the early epiphany by Barber et al. showed that PD-1 blockade restored T cell effector function in chronic LCMV infection https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts"> https://rdcu.be/cjx3X ">https://rdcu.be/cjx3X&quo...
4/ But this seminal study showed reversal of exhaustion at the "population" level so it did not definitively show a restoration of function of the "already exhausted" T cells per se

(I hope this tweet is clear, I feel like I opsonized myself for phagocytic responses)
5/ This point was further elucidated by K. Pauken et al (2012) that Tex were epigenetically stable and that PD-1 blockade only transiently restores effector function only for these cells to succumb to the exhausted fate
https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts"> https://science.sciencemag.org/content/354/6316/1160">https://science.sciencemag.org/content/3...
Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade

During cancer or chronic infection, T cells become dysfunctional, eventually acquiring an “exhausted” phenotype. Immunotherapies aim to reverse this state. Using a mouse model of chronic infection,...

https://science.sciencemag.org/content/354/6316/1160
6/ To add to our confusion, Wherry and co. that PD-1 deficiency ENHANCES T cell exhaustion

https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts"> https://rupress.org/jem/article/212/7/1125/41837/Genetic-absence-of-PD-1-promotes-accumulation-of">https://rupress.org/jem/artic...
7/ So...We know that PD-1 blockade has a clinical therapeutic benefit in T cell responses

Again, what& #39;s the mechanism?
8/ Several interesting recent answers:

First, H. Chang and M. Davis& #39; groups showed that PD-1 blockade did not reinvigorate exhausted T cells but promoted the expansion of new tumor-specific T cell clones

https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts"> https://www.nature.com/articles/s41591-019-0522-3

This">https://www.nature.com/articles/... was a defining moment in the field
9/ Thanks to paired scTCR sequencing and GE
10/ An equally important discovery was made by @SamirNKhleif& #39;s group showing that PD-1 blockade in the absence of optimal T cell stimulation (e.g. vaccine, inflammation...etc) leads to worse outcomes than no blockade

https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts"> https://www.nature.com/articles/s41590-019-0441-y">https://www.nature.com/articles/...
11/ This was recently demonstrated by Skokos and co. @Regeneron showing that PD-1 blockade prior to irradiation can abrogate antitumor immunity

https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts"> https://immunology.sciencemag.org/content/6/58/eabg0117">https://immunology.sciencemag.org/content/6...
Sequence of αPD-1 relative to local tumor irradiation determines the induction of abscopal antitu...

Immune checkpoint blockade is clinically successful in various cancer types, yet many treated patients recur; thus, determining effective combination therapies that induce systemic antitumor immunity...

https://immunology.sciencemag.org/content/6/58/eabg0117
12/ All stressing the fact that you need optimal T cell priming and response before you block PD-1
13/ Last but not least, V. Boussiotis and co. showed [surprisingly] that PD-1 deletion on myeloid cells promotes antitumor immunity, upending the paradigm that the impact of PD-1 blockade is primarily T cell-mediated.

https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts"> https://immunology.sciencemag.org/content/5/43/eaay1863">https://immunology.sciencemag.org/content/5...
14/ Therefore, PD-1 leads more than a double life as a regulatory protein and we are likely to discover more roles.

And will keep adding to this drawing

"A Cure Within" p.35 -Tasuko Honjo
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