Summary Plasminogen activator inhibitor-1 (PAI-1) has a pro-tumorigenic function via its pro-angiogenic and anti-apoptotic activities. Here we demonstrate that PAI-1 promoted the recruitment and M2 polarization of monocytes/macrophages through different structural domains. Its LRP1 interacting domain regulated macrophage migration, while its C-terminal uPA interacting domain promoted M2 macrophage polarization through activation of p38MAPK and NF-κB and induction of an autocrine IL-6/STAT3 activation pathway. We then show in several experiments in mice, that expression of PAI-1 is associated with increased tumorigenicity, increased presence of M2 macrophages, higher levels of IL-6 and increased STAT3 phosphorylation in macrophages. Strong positive correlations between PAI-1, IL-6 and CD163 (M2 marker) expression were also found by meta-analysis of transcriptome data in many human cancers. Altogether, these data provide evidence for a mechanism explaining the paradoxical pro-tumorigenic function of PAI-1 in cancer.

Heterogeneous prostatic carcinoma-associated fibroblasts (CAF) contribute to tumor progression and resistance to androgen signaling deprivation therapy (ADT). CAF subjected to extended passaging, compared to low passage CAF, were found to lose tumor expansion potential and heterogeneity. Cell surface endoglin (CD105), known to be expressed on proliferative endothelia and mesenchymal stem cells, was diminished in high passage CAF. RNA-sequencing revealed SFRP1 to be distinctly expressed by tumor-inductive CAF, which was further demonstrated to occur in a CD105-dependent manner. Moreover, ADT resulted in further expansion of the CD105 fibroblastic population and downstream SFRP1 in 3-dimensional cultures and patient-derived xenograft tissues. In patients, CD105 fibroblasts were found to circumscribe epithelia with neuroendocrine differentiation. CAF-derived SFRP1, driven by CD105 signaling, was necessary and sufficient to induce prostate cancer neuroendocrine differentiation in a paracrine manner. A partially humanized CD105 neutralizing antibody, TRC105, inhibited fibroblastic SFRP1 expression and epithelial neuroendocrine differentiation. In a novel synthetic lethality paradigm, we found that simultaneously targeting the epithelia and its microenvironment with ADT and TRC105, respectively, reduced castrate-resistant tumor progression, in a model where either ADT or TRC105 alone had little effect.

BackgroundLocally advanced pancreatic cancer (LAPC) has a dismal prognosis with current treatment modalities and one-third of patients die from local progression of disease. Preclinical studies with orthotopic PC demonstrated dramatic synergy between radiotherapy (RT) and the poly(ADP-ribose) polymerase-1/2 inhibitor (PARPi), veliparib. We conducted a phase I trial of gemcitabine, radiotherapy and dose-escalated veliparib in LAPC.MethodsThis was a single institution investigator-initiated open-label, single-arm phase 1 clinical trial (NCT01908478). Weekly gemcitabine with daily IMRT and veliparib dose escalated using a Bayesian adaptive design were administered in treatment naïve LA or borderline resectable PC. The primary end point was identification of the MTD. Secondary endpoints included efficacy, characterization of PAR levels using ELISA, DDR alterations with targeted next generation sequencing and transcriptome analysis, tumor mutation burden (TMB) and microsatellite instability (MSI) status.FindingsThirty patients were enrolled. The MTD of veliparib was 40 mg BID with gemcitabine 400 mg/m2 and RT (36 Gy/15 fractions). Sixteen DLTs were identified in 12 patients. Grade ≥ 3 adverse events included lymphopenia (96%) and anemia (36%). Median OS for all patients was 15 months. Median OS for DDR pathway gene altered and intact cases was 19 months (95% CI: 6.2–27.2) and 14 months (95% CI: 10.0–21.8), respectively. There were no significant associations between levels of PAR, TMB, or MSI with outcomes. The DDR transcripts PARP3 and RBX1 significantly correlated with OS.InterpretationThis is the first report of a PARPi-chemoradiotherapy combination in PC. The regimen was safe, tolerable at the RP2D, and clinically active as an upfront treatment strategy in patients biologically unselected by upfront chemotherapy. Expression of the DDR transcripts, PARP3 and RBX1, were associated with OS suggesting validation in a follow up phase 2 study.FundPhase One Foundation; National Institutes of Health [1R01CA188480-01A1, P01 CA098912]. Veliparib was provided by Abbvie.

There is growing interest in identifying predictive biomarkers for inhibitors of programmed cell death protein 1 receptor (PD‐1), programmed death ligand 1 (PD‐L1), and cytotoxic T‐lymphocyte associated protein 4 (CTLA‐4). Given the links between the stool microbiota, anticancer immunosurveillance, and general health, the composition of the gut microbiome has recently undergone investigation as a biomarker for immunotherapy. In this review, we highlight published results from preclinical and clinical studies to date supporting a relationship between the gut microbiome and antitumor efficacy of immune checkpoint inhibitors. Despite the promising and hypothesis‐generating findings that have been produced in this arena to date, there remain some inconsistencies amongst present data that may need to be resolved to contribute to further development. Among these, a better understanding of the immunomodulatory function of the microbiome, standardization in sampling, sequencing techniques, and data analysis, and ensuring uniformity across various aspects of study design are warranted in conducting future prospective studies seeking to validate the gut microbiome as a potential biomarker of response to checkpoint blockade.