DPP inhibition alters the CXCR3 axis and enhances NK and CD8+ T cell infiltration to improve anti-PD1 efficacy in murine models of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer death in the USA by 2030. Immune checkpoint inhibitors fail to control most PDAC tumors because of PDAC's extensive immunosuppressive microenvironment and poor immune infiltration, a phenotype also seen in other non-inflamed (ie, 'cold') tumors. Identifying novel ways to enhance immunotherapy efficacy in PDAC is critical. Dipeptidyl peptidase (DPP) inhibition can enhance immunotherapy efficacy in other cancer types; however, the impact of DPP inhibition on PDAC tumors remains unexplored. METHODS: We examined the effects of an oral small molecule DPP inhibitor (BXCL701) on PDAC tumor growth using mT3-2D and Pan02 subcutaneous syngeneic murine models in C57BL/6 mice. We explored the effects of DPP inhibition on the tumor immune landscape using RNAseq, immunohistochemistry, cytokine evaluation and flow cytometry. We then tested if BXCL701 enhanced anti-programmed cell death protein 1 (anti-PD1) efficacy and performed immune cell depletion and rechallenged studies to explore the relevance of cytotoxic immune cells to combination treatment efficacy. RESULTS: In both murine models of PDAC, DPP inhibition enhanced NK and T cell immune infiltration and reduced tumor growth. DPP inhibition also enhanced the efficacy of anti-PD1. The efficacy of dual anti-PD1 and BXCL701 therapy was dependent on both CD8+ T cells and NK cells. Mice treated with this combination therapy developed antitumor immune memory that cleared some tumors after re-exposure. Lastly, we used The Cancer Genome Atlas (TCGA) to demonstrate that increased NK cell content, but not T cell content, in human PDAC tumors is correlated with longer overall survival. We propose that broad DPP inhibition enhances antitumor immune response via two mechanisms: (1) DPP4 inhibition increases tumor content of CXCL9/10, which recruits CXCR3+ NK and T cells, and (2) DPP8/9 inhibition activates the inflammasome, resulting in proinflammatory cytokine release and Th1 response, further enhancing the CXCL9/10-CXCR3 axis. CONCLUSIONS: These findings show that DPP inhibition with BXCL701 represents a pharmacologic strategy to increase the tumor microenvironment immune cell content to improve anti-PD1 efficacy in PDAC, suggesting BXCL701 can enhance immunotherapy efficacy in 'cold' tumor types. These findings also highlight the potential importance of NK cells along with T cells in regulating PDAC tumor growth.

A Novel Urine Exosome Gene Expression Assay to Predict High-grade Prostate Cancer at Initial Biopsy.

IMPORTANCE: Overdiagnosis and overtreatment of indolent prostate cancer (PCA) is a serious health issue in most developed countries. There is an unmet clinical need for noninvasive, easy to administer, diagnostic assays to help assess whether a prostate biopsy is warranted. OBJECTIVE: To determine the performance of a novel urine exosome gene expression assay (the ExoDx Prostate IntelliScore urine exosome assay) plus standard of care (SOC) (ie, prostate-specific antigen [PSA] level, age, race, and family history) vs SOC alone for discriminating between Gleason score (GS)7 and GS6 and benign disease on initial biopsy. DESIGN, SETTING, AND PARTICIPANTS: In training, using reverse-transcriptase polymerase chain reaction (PCR), we compared the urine exosome gene expression assay with biopsy outcomes in 499 patients with prostate-specific antigen (PSA) levels of 2 to 20 ng/mL. The derived prognostic score was then validated in 1064 patients from 22 community practice and academic urology clinic sites in the United States. Eligible participants included PCA-free men, 50 years or older, scheduled for an initial or repeated prostate needle biopsy due to suspicious digital rectal examination (DRE) findings and/or PSA levels (limit range, 2.0-20.0 ng/mL). MAIN OUTCOMES AND MEASURES: Evaluate the assay using the area under receiver operating characteristic curve (AUC) in discrimination of GS7 or greater from GS6 and benign disease on initial biopsy. RESULTS: In 255 men in the training target population (median age 62 years and median PSA level 5.0 ng/mL, and initial biopsy), the urine exosome gene expression assay plus SOC was associated with improved discrimination between GS7 or greater and GS6 and benign disease: AUC 0.77 (95% CI, 0.71-0.83) vs SOC AUC 0.66 (95% CI, 0.58-0.72) (P < .001). Independent validation in 519 patients' urine exosome gene expression assay plus SOC AUC 0.73 (95% CI, 0.68-0.77) was superior to SOC AUC 0.63 (95% CI, 0.58-0.68) (P < .001). Using a predefined cut point, 138 of 519 (27%) biopsies would have been avoided, missing only 5% of patients with dominant pattern 4 high-risk GS7 disease. CONCLUSIONS AND RELEVANCE: This urine exosome gene expression assay is a noninvasive, urinary 3-gene expression assay that discriminates high-grade (≥GS7) from low-grade (GS6) cancer and benign disease. In this study, the urine exosome gene expression assay was associated with improved identification of patients with higher-grade prostate cancer among men with elevated PSA levels and could reduce the total number of unnecessary biopsies.