Abbas Nazir

Prostate cancer (PCa) is a lethal malignancy that displays profound resistance to immune checkpoint blockade (ICB), via mechanisms that are poorly understood. Here, we investigate the causes of CD8 T cell exhaustion and mechanisms of tumor progression in a PCa animal model, by single cell and spatial profiling, along a time course, following orthotopic transplantation of RB1/TP53/PTEN-deficient mouse organoids, competent to express neoantigens. The resulting tumors were castration resistant, consisting of largely basal and L2 malignant cells with upregulated inflammatory gene programs, and a specific spatial distribution of macrophages, cancer associated fibroblast (CAF) subtypes, and CD8 T-cells that was not previously reported. Using Zman-seq, we demonstrate that the effector function of tumor-infiltrating CD8 T cells was rapidly impaired as early as 24hrs after their infiltration, likely driven by signals from proinflammatory macrophages, Ccl2 - Jak2 ⁺ inflammatory CAFs, and malignant basal cells, thus driving resistance to ICB. Interestingly, dual blockade of JAK1/2 and PD1 induced potent anti-tumor effects in tumor epithelial cells, decreased malignant epithelial cells and pro-inflammatory macrophages, and increased the proportion of normal ( Pi16 ⁺ ) fibroblasts in the TME. Our results underscore the therapeutic potential of targeting JAK1/2 to enhance the efficacy of ICB, providing a rationale for clinical investigation of this combination in PCa.

Patient characteristics for scATAC-Seq

ATAC-Seq analysis - MPN vs. TAM

Patient characteristics for scATAC-Seq

Phenotypic characterization and Jak2V617F oncogenic dependency in the setting of concomitant Tet2 loss

Functional characterization of Jak2RL knock-in/knock-out in vivo

Assessment of tamoxifen toxicity on Jak2RL knock-in cells

Differential responses of Jak2V617F deletion compared to JAK inhibitor therapy in vivo

Effects of Jak2V617F deletion on MPN stem cell fitness and disease transplantability

RNA-Seq analysis - MPN vs. TAM