Heterogeneity in tumor-intrinsic sensitivity to interferon gamma stimulation

---

Presentation Time: 05:45 PM - 06:00 PM
Abstract ID: 5580 - B

Presenting Author:
Elliot Merritt , Senior Scientist at Icahn Sch. of Med., Mount Sinai

Abstract:

Interferon gamma (IFNg) drives resistance to PD1-targeting immunotherapies by altering the tumor-intrinsic immune phenome associated with the upregulation of inhibitory ligands and immunosuppressive mediators. Major bottleneck to improving the efficacy of IFNg-inducing immunotherapies is our lack of knowledge as it pertains to tumor-intrinsic features that drive tumor-specific differences in IFNg sensitivity. There is a critical need to define the cellular and molecular mechanisms underlying tumor-intrinsic sensitivity to IFNg in pre-clinical models that reproduce the oncogenic programs of human tumors.

We leveraged patient-derived tumor organoids (PDO) with high-dimensional immunophenotyping and RNA-sequencing to determine IFNg sensitivity across different tumors. Our approach identified significant differences in IFNg sensitivity between malignant cells of the same tumor associated with the expression of therapeutically relevant immune checkpoints and secreted proteins. These differences were driven by unique malignant programs underlying patient-specific intratumoral divergence in IFNg sensitivity.

PDO model intra-tumoral and inter-patient heterogeneity in IFNg sensitivity. This is the first study to reveal how the underlying oncogenic pathways intersect with sensitivity to IFNg stimulation and uncover the breadth of IFNg-induced molecular programs in patient tumors.