Thread by @TheVinodLab

Today, in @Nature, we reveal PART 2 of our investigations on

“What IS going on in long-term survivors of #PancreaticCancer (#PDAC)?”

“Is it REALLY the immune system?”

Well…more evidence here - > nature.com/articles/s4158…

Thread below [1/30]

In 2017, we reported in @Nature here -> nature.com/articles/natur… -> that primary tumors of long-term survivors of #PDAC had ~12x more activated CD8 T cells vs. short-term survivors. Now, others had reported this before - but we wanted to know:

“What are the antigens?”

Here, the prevailing belief was:

#PDAC has few mutations -> even fewer mutation-derived neoantigens -> neoantigens are unlikely T cell antigens in #PDAC.

But we thought: despite #PDAC’s few mutations, mutation-derived neoantigens may still be T cell antigens in #PDAC survivors

As we explored this, we found early that long-term (like short-term) #PDAC survivors had only ~40 neoantigens.

And, these neoantigens arose mostly in tumor-specific passenger mutations that generated single amino acid substitutions, not in shared (KRAS, MMR, BRCA1/2) mutations.

So if neoantigens were T cell antigens in long-term #PDAC survivors, we would almost certainly have to identify them based on conserved features or “qualities” that render such neoantigenic substitutions immunogenic.

Now, on a broader level, like in #PDAC survivors, most neoantigens in human cancer also arose in single amino acid substitutions - quite literally the smallest unit protein-coding genomic change – of which only <10% are in fact immunogenic.

So, we thought if T cells can recognize such exquisite changes, this probably represents a broader conserved strategy of how T cells surveil the genome for errors.

And if we can capture the features that T cells recognize in such errors, through what we called the “#NeoantigenQualityModel”, we could both understand the underlying biology and potentially apply it in therapies (eg: rationally select antigens for vaccines).

So, in 2017, we proposed our #NeoantigenQualityModel v1.0.

Here, we estimate if a neoantigen is immunogenic based on features of

a. Non-selfness – by neoantigen similarity to known antigens
b. Selfness – by how the neoantigen differentially binds the MHC vs. its wild type

With #NeoantigenQualityModel v1.0, we showed long-term #PDAC survivors had tumors enriched in high quality neoantigens.

Essentially, that classifying tumors (#PDAC, #lungcancers, #melanomas nature.com/articles/natur…) based on “neoantigenicity” correlated with prognosis.

So, this was interesting – but we wanted more evidence that neoantigens were T cell antigens in long-term #PDAC survivors.

So – if high quality neoantigens are targeted in primary tumors, they should be removed, or “immune edited” in recurrent tumors, right?

Today’s paper addresses these questions - nature.com/articles/s4158…

a) Are neoantigens edited in long-term #PDAC survivors?
b) If so, are the edited neoantigens high quality?

Now, re: a) – we thought this question also addresses a broader ? in #tumorimmunology – does cancer immunoediting occur spontaneously in humans?

We’ve known it occurs in 🐁 by studying how tumors evolve longitudinally in immune proficiency/deficiency.

But what about humans?

We thought evidence in humans would similarly require longitudinal studies of how tumors evolve under different immune pressures over time.

And #PDAC - though classically “immune cold” - could paradoxically be the ideal tumor to test #cancerimmunoediting (reasons in the paper).

So - thanks to @ciacobu @CpcrMsk - we tracked how #PDACs evolved from primary tumors to recurrence in long-term survivors (greater immune pressure) and short-term survivors (lesser immune pressure).

In total – we tracked how 70 tumors evolved over 10 years.

We found (SPOILER ALERT)

….that though tumors in long-term #PDAC survivors had more time to evolve, they in fact developed genetically less heterogeneous tumors with fewer neoantigens compared to short-term survivors.

Interesting..

but are these neoantigens that are not acquired in long-term #PDAC survivors just

any neoantigens/mutations (arguing against immunoediting)

or

immunogenic “high quality neoantigens (arguing for immunoediting)?

So, we developed #NeoantigenQualityModel v2.0…

Here, we estimate if a neoantigen is immunogenic based on features of

a.Non-selfness – by neoantigen similarity to known antigens

b. Selfness – as the antigenic distance needed for a neoantigen to differentially bind the MHC + activate a T cell compared with its wild-type

Broader idea here is that most neoantigenic substitutions will in fact be too antigenically similar to its wild-type -> thus won’t be immunogenic (hence perhaps why only <10% of neoantigens are immunogenic).

With this #NeoantigenQualityModel v2.0, we found that the long-term #PDAC survivors in fact evolved tumors with far fewer high quality neoantigens (arguing for immunoediting)

So, take home messages are

1. We think this = evidence that immunoediting occurs in human cancer

(we found it interesting that this is revealed in #PDAC, the classic “immune cold” tumor)

2. Editing targets high quality neoantigens defined by the #NeoantigenQualityModel

What are the implications?

Well, implications for biology

We think the #NeoantigenQualityModel captures the features that the immune system recognizes to preserve the integrity of host genome.

And implications for #PDAC therapy

More evidence that neoantigens are T cell antigens in long-term survivors.

So, if high-quality neoantigens spontaneously stimulate immunity that correlates with longer survival

AND

Nearly all PDACs harbor neoantigens, then…

Can vaccines render neoantigens immunogenic -> spark immunity in #PDAC

Find out @ #ASCO22 – where we @genentech @BioNTech_Group reveal results of our trial to treat #PDAC with #mRNA neoantigen vaccines.

clinicaltrials.gov/ct2/show/NCT04…

And implications for #immunotherapy

#NeoantigenQualityModel could allow rational antigen selection for vaccines (for cancers + possibly other diseases)

A nice summary of today’s paper is here  mskcc.org/news/picking-w…

The “we” here is many – Zach Sethna & Luis Rojas, outstanding postdoctoral scientists in @TheVinodLab; the incredible @MartaLuksza @bengrbm, my partners in science; everyone in our eclectic group that love tumor immunology, medicine, and physics – but that all HATE #PDAC.

PLUS phenomenal collaborators at @ENS_ULM @imperialcollege @GarvanInstitute @CompOncMSK @IcahnMountSinai @parkerici @CpcrMsk

So PROUD of our group!!

AND huge thank you to our incredibly supportive funders

@SU2C @lustgartenfdn who initiated this idea to bring together scientists, doctors, and physicists! @DamonRunyon who supported @TheVinodLab when we began studying long-term #PDAC survivors, @psscra

And lastly and most importantly – all the patients! Thank you for your ceaseless bravery and commitment to research! You inspire us!

And that’s a wrap!

And here is a shareable PDF link!

rdcu.be/cNVt6