# Reconstruction of T cell infiltration in an osteosarcoma PDX-organoid interactive biobank for personalized immunotherapy

## TL;DR

Researchers created a biobank of osteosarcoma organoids linked to patient tumors and immune cells to test personalized immunotherapies and identify effective drug combinations.

## Contribution

A novel PDX-organoid biobank is developed to model immune infiltration and test immunotherapy responses in osteosarcoma.

## Key findings

- PDX-derived organoids maintain spatial and genomic features of osteosarcoma tumors.
- Co-culturing with PBMCs enables T cell infiltration and immune response modeling in organoids.
- PRMT5MTA inhibition improves immunotherapy response in chromosome 9p21.3-deleted osteosarcoma.

## Abstract

Osteosarcoma (OS) is an aggressive malignant bone tumor with limited therapeutic options and low response to immunotherapy. OS rarity slows clinical translation, highlighting the need for models that bridge patient-derived xenograft (PDX) systems and next-generation platforms. Here, we establish an OS PDX-organoid interactive biobank by self-assembling single-cell suspensions into individualized OS organoids (iOSs). iOS models recapitulate OS spatial and architectural features at millimeter scale in vitro and as xenografts and maintain functional pairing with matched PDX models. We validate iOS fidelity using histopathology, spatial features, genomics, transcriptomics, and pharmacogenomics. By reconstructing T cell infiltration in PDX-derived iOS models, we model treatment-associated immune responses and support immunotherapy translational studies. Using paired iOS-PDX models, we show that a PRMT5MTA inhibitor enhances immunotherapy response in chromosome 9p21.3-deleted OS.

•A PDX-organoid biobank captures inter-patient heterogeneity in osteosarcoma•PBMC co-culture rebuilds T cell infiltration and functional immune readouts in organoids•Immune-reconstructed iOS drug testing aligns with patient-specific therapeutic response•Chr9p21.3/MTAP loss marks vulnerability to APRN2169 plus PD-1 blockade

A PDX-organoid biobank captures inter-patient heterogeneity in osteosarcoma

PBMC co-culture rebuilds T cell infiltration and functional immune readouts in organoids

Immune-reconstructed iOS drug testing aligns with patient-specific therapeutic response

Chr9p21.3/MTAP loss marks vulnerability to APRN2169 plus PD-1 blockade

Sun et al. establish a PDX-linked osteosarcoma organoid biobank and rebuild immune infiltration by co-culturing organoids with human PBMCs. This platform connects tumor genotype and immune context to therapeutic response, enabling ex vivo drug testing and supporting a precision combination strategy for Chr9p21.3/MTAP-deleted osteosarcoma.