卡博替尼重塑胰腺肿瘤微环境以增强免疫治疗

Background: Despite decades of research, pancreatic ductal adenocarcinoma (PDAC) is still among the most lethal cancers, with a 5-year survival rate of less than 12%. Most patients with advanced or metastatic disease, and even those eligible for potentially curative resection face experiencing local or distant recurrence within two years of diagnosis. Earlier studies by our research team reported that the infiltration of polymorphonuclear-myeloid derived suppressor cells (PMN-MDSCs) within the PDAC tumor microenvironment (TME) inhibit T cell effector function. These studies were the foundation for the development of a Phase II Trial evaluating the safety and efficacy of atezolizumab in combination with cabozantinib for the treatment of metastatic, refractory PDAC (NCT04820179). Hypothesis: Using the longitudinal biospecimens collected and processed from the Phase II atezolizumab/cabozantinib clinical trial, we hypothesized that Cabozantinib (Cabo) increases the efficacy of immunotherapy by reprogramming the cancer associated fibroblasts (CAFs), depleting MDSCs and increasing CD8 cytotoxic T lymphocyte infiltration within the TME. Methods: Longitudinal core biopsies were collected from patients enrolled in the Phase II trial pre-treatment and 9 weeks on combinatorial treatment with Cabo and Atezolizumab (Atezo) using the Rarecyte Orion ™ Multiplex Immunofluorescence (MxIF) and CosMx ™ Spatial Molecular Imager (CosMx ™ SMI). MxIF images were curated into Minerva Stories (https://uga-som-imtm.github.io/009_010/) for interactive data. Patient derived organoids (PDOs) were generated harboring CAFs were co-cultured with autologous immune cells (IMM) to predict the patient response Cabo/Atezo combinatorial therapy. Results: CosMx ™ SMI analysis revealed that the TME of patients exhibiting stable disease or partial response in response to Cabo/Atezo correlated with depletion of the MDSCs and a reprogrammed CAF phenotype leading to an infiltration of granzyme+ CTLs. Patients with progressive disease exhibited a TME with persistent infiltration of CD11b+MDSCs, desmoplastic stroma consisting of inflammatory CAFs and therapy resistant cancer stem cells (CSCs) expressing CD44v9. MxIF showed that among the predominant cell types that persisted through disease stages were Schwann cells, CSCs, Tregs, a diverse phenotype of CAFs, MDSCs, and acinar and ductal cells, of which a subset were identified as undergoing acinar-to-ductal metaplasia. PDO/CAF/IMM co-cultures treated with Cabo/Atezo led to a depletion of MDSCs and CAFs with a significant increase in CTL proliferation, effector function and tumor cell death that was predictive of the patient's response to combination therapy. Conclusion: Spatial biology and organoid technologies have revealed a multitargeted effect of Cabo in reprogramming the TME and potential optimization of the efficacy of Atezo in PDAC patients.