Benjamin D. Greenbaum

Thank you @the_IAS for allowing me to share how #IAS shaped my winding path from physics -> working on #mRNA vaccines in cancer @CompOncMSK @MSKCancerCenter.

As theme for my research I landed on "What is Non-self?". With @TheVinodLab @MartaLuksza & others
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✨ Excited to share new work in @NatureGenet, with next-door neighbor @SohrabShah! Our labs – led by @nceglia; @GreedyApple; Zach Sethna; and @elhanati_yuval - applied information theory and probabilistic modeling to the question of how T cell dynamics changes in response to immunotherapy, particularly coupling between a T cell's T cell receptor (TCR) and its phenotypic state.

T cell responses are critical to cancer immunotherapies. Their behavior is often strongly influenced by their TCR, which directly engages with antigens presented on the cell surface. How clonal the sequenced TCR repertoire is in a dataset has been used to understand response – TCRs that recognize an antigen multiply – but its often a noisy measure, and we wanted to extend this logic to single-cell data in an eqiposed way. Information theory offers a solution.

The specific question of how information is propagated between the TCR and its phenotypic state also becomes a general way to probe genotype-phenotype mapping. The mutual information between receptor and state - that is how much knowing about one tells you information about the other - and how that changes can then be used to probe therapeutic response. Given data sparsity this becomes a problem in probabilistic inference – which was addressed here via a cool hierarchical Bayesian framework led by @GreedyApple & @nceglia.

A flux in phenotype and stronger mutual information post-treatment was associated with response to immunotherapy. In non-responders, therapy did not improve poor communication between TCR and phenotype. Hence information dynamics can be used to measure response.

We are already collectively using this approach across many, many projects. We use variants to analyze vaccine data with @TheVinodLab at the Olayan Center for Cancer Vaccines @MSKCancerCenter, in multiple projects with @break_cancer, throughout the Halvorsen Center @CompOncMSK, and elsewhere. It was a lot of fun and we hope you enjoy! Code link included! 👇 👇 👇

nature.com/articles/s4158…

Understanding which antigens are targetable in a tumor forms the basis for personalized immunotherarapies, which just got a big boost from the recent announcement by @moderna_tx at @myESMO.

We are excited to share a timely perspective on this topic with @TheVinodLab & Zach Sethna the Olayan Center for Cancer Vaccines @MSKCancerCenter out now in @Cancer_Cell. We discuss the theoretical basis of neoantigen quality, which alterations in a tumor the immune system targets, within the theory of what is nonself. This topic has been one of discussion for us for over a decade.

Several paradoxes emerge, in particular, that viruses inhabit spaces close to self. So the immune system likely surveils close to self antigens, like we see in cancer, in order to fight viruses which exert strong evolutionary pressure (shout out to @JonAvramLevine & @andimscience). A model which captures one can therefore inform the other.

Lots of work to do! Enjoy the work below 👇👇👇

sciencedirect.com/science/articl…

PS - If you like science of this sort and are looking for a postdoc consider our Theory Group effort at @MSKCancerCenter: careers.mskcc.org/vacancies/9847…

Great collaboration with @CentralParkWMD @MarcHilmi @EileenMOReilly @ciacobu @schoenfeld_j
@MckerrowWilson & an incredible team 👇👇👇

biorxiv.org/content/10.648…

The broader immunologic point from this work is the distinction between systemic activation and tissue-effective immunity. Neoantigen recognition by specific T-cell receptor, clonal expansion and spatial context all matter and the tumor ecosystem can determine whether a T-cell response becomes effective. From studies like this we will learning more about the fundamental rules of T-cell engagement in cancer and how to translate for precision immunotherapies, such as cancer vaccines, to help more patients.

@MSKCancerCenter

Exciting news!

merck.com/news/merck-and…