Multimodal investigation of myeloma-recognizing T cells, their transcriptional features and clinical relevance

Description

T cells play a critical role in immune surveillance against multiple myeloma (MM), yet their spontaneous
reactivity to MM remains poorly understood. This project aims to systematically investigate MM-recognizing T cells, their transcriptional profiles, and their clinical relevance, with the goal of advancing immunotherapeutic strategies for MM and providing a computational tool to the community to rapidly identify MM antigen-specific T cells de novo.
In Aim 1, we will employ multimodal transcriptomic, proteomic, and functional profiling to characterize the immunological synapse between MM cells and T cells. By integrating single-cell RNA and TCR sequencing with MHC immunopeptidomics, we will map MM-infiltrating T cell repertoires and identify MM-specific and shared antigen-reactive T cells. Functional validation through antigen-agnostic and antigen-specific ex vivo assays will reveal distinct phenotypic and functional attributes of MM-reactive T cells compared to bystander T cells.
In Aim 2, we will derive transcriptomic signatures of experimentally validated MM-reactive T cells to predict anti-MM reactivity and assess their utility as biomarkers for treatment monitoring. Using neural network-based bioinformatic tools, we will quantify the anti-MM potential of T cells across clinical modalities. These findings will support the identification of personalized MM-reactive TCRs, enabling rapid development of TCR-based therapies and expanding therapeutic options for MM patients.
Preliminary results from an exploratory cohort demonstrate the feasibility of our workflow, identifying shared cancer-associated antigens and distinct transcriptional signatures of MM-reactive T cells. These insights provide a foundation for a clinically relevant platform for MM TCR discovery and functional characterization. This project will deliver a comprehensive roadmap of MM-specific T cell immunity, aiming to pave the way for innovative T cell-based therapies and biomarkers in MM.