Grégoire Altan-Bonnet

Colloquium with Grégoire Altan-Bonnet‍

Deputy Chief, Laboratory of Integrative Cancer Immunology, National Cancer Institute

Monday, March 9, 2026

4:00 - 5:00 pm (refreshments st 3:30 pm)

Monadnock (Broad Institute, 415 Main St., room 2040*) and virtually at broad.io/ewsc

*If you do not have a Broad badge, please arrive 10 minutes early with a different ID to register with security and be escorted up to Monadnock.

Abstract:

Cancer immunotherapies elicit highly variable outcomes in patients and genetically identical mouse models, suggesting a strong intrinsic stochastic component. Using thousands of well-controlled ex vivo immunoassays, we show that leukocyte activation and tumor cytotoxicity display macroscopic variability that follows a shifted Poisson distribution. This variability arises from stochastic activation of a rare subpopulation of T cells (“Spark T cells”) coupled to a paracrine IFN-γ–driven positive feedback. By integrating these quantitative insights into a custom machine-learning pipeline with single-cell resolution, we phenotypically and functionally identify Spark T cells in murine naïve T cells and in human T cell blasts used for adoptive cell therapy, and demonstrate their role in shaping heterogeneous immunotherapy responses [http://dx.doi.org/10.2139/ssrn.4996071]. Building on this framework, we investigate how receptor-level signal integration modulates T cell potency and specificity. While chimeric antigen receptor (CAR) T cells show strong cytotoxicity but limited specificity in solid tumors, endogenous T cell receptors (TCRs) provide exquisite antigen discrimination with reduced efficacy. Deploying our high-throughput platform and mathematical modeling [PMID: 35587980], we reveal inhibitory and cooperative crosstalk between co-expressed TCRs and CARs: strong TCR–antigen interactions enhance CAR activation, whereas weak interactions antagonize it. Leveraging this crosstalk, we engineer dual TCR/CAR T cells targeting neoantigens and HER2 that exhibit enhanced antitumor activity with minimal off-tumor toxicity in a humanized solid tumor mouse model [PMID: 40220754] Together, these results show how stochastic T cell activation and receptor-level signal integration jointly govern variability, potency, and precision in cancer immunotherapy.