Abstract 1582: Cabozantinib changes the tumor microenvironment to increase the efficacy of immunotherapy in refractory metastatic pancreatic ductal adenocarcinoma
Authors: Jayati Chakrabarti, Pritha Adhikary, Jiang Wang, Davendra Sohal, Syed A. Ahmad, Junaid Arshad, Aaron J. Scott, Rachna T. Shroff, Yana Zavros
Journal: Cancer Research (2024)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Tumors evade immune surveillance by expressing PD-L1 that interacts with the T cell protein PD-1, subsequently inhibiting CD8+ cytotoxic T lymphocyte proliferation and effector function. A plausible reason for this observation may be that other, redundant, immune suppressive mechanisms are at play. Our research team has shown that elevated infiltration of polymorphonuclear (PMN)-MDSCs within the PDAC tumor microenvironment (TME) inhibit T cell effector function, regardless of PD-1/PD-L1 inhibition (Holokai et al., 2020). Objective: A Phase II clinical trial was developed to identify the potential therapeutic benefit of combinatorial anit-PD-L1/PD-1 and cabozantinib (cabo) treatment in therapy-resistant (refractory and metastatic) PDAC patients. Methods: NanoString CosMx™ spatial molecular transcriptomic imaging (CosMx™ SMI) was performed using FFPE sections collected from a liver or lung metastatic target lesions at visit 1 (pretreatment) and visit 2 (9 weeks on combinatorial treatment) from individual patients. FFPE sections were prepared from the same target lesion, and fields of view were chosen on the H&amp;E in consultation with GI pathologist. Seurat V 4.0 was used for the analysis and visualization by spatial mapping of each FOV showing identified cell population indicated by color coding in visit 1 and visit 2 within the same patient. Multiplex immunofluorescence (MxIF) of patient FFPE tissues and single cell RNA sequencing (scRNAseq) of PDAC organoids (PDOs) generated from the core biopsies collected at visit 1 and matched visit 2 from each patient were used to validate the CosMx™ SMI data. Results: A uniform manifold approximation and projection showed loss of tumor cell populations within the PDAC TME in response to combinatorial treatment compared to pretreatment visit 1. Comparison between spatial maps of visit 1 to visit 2 demonstrated a shift in cell populations within defined NICHES (local cellular TME) whereby there was 1) a loss of tumor cell populations, 2) increase in CTL infiltration, 3) increase in endothelial cells, 4) decrease immunosuppressive MDSCs, 5) decrease in antigen presenting CAFs, and 6) change in myCAFs to an inflammatory CAF phenotype. Within the iCAF population IL-6, CXCL1, LIFR, ACTA2 and FAK were expressed; correlating with an increase in CD8 perforin and granzyme B positive cells in response to cabo and checkpoint inhibition. MxIF, spectral flow cytometry and scRNAseq analyses of the matched in vitro PDO model showed tumor cell death that correlated with decreased MDSC viability, increased CTL proliferation and a shift in CAF phenotypes. Conclusion: These findings suggest that cabo induces a TME conducive to increased response to immunotherapy in PDAC patients with refractory metastatic disease. Citation Format: Jayati Chakrabarti, Pritha Adhikary, Jiang Wang, Davendra Sohal, Syed A. Ahmad, Junaid Arshad, Aaron J. Scott, Rachna T. Shroff, Yana Zavros. Cabozantinib changes the tumor microenvironment to increase the efficacy of immunotherapy in refractory metastatic pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1582.