Innate inflammation promotes tumor development, although the role of innate inflammatory cytokines in established human tumors is unclear. Herein, we report clinical and translational results from a phase Ib trial testing whether IL1β blockade in human pancreatic cancer would alleviate myeloid immunosuppression and reveal antitumor T-cell responses to PD1 blockade. Patients with treatment-naïve advanced pancreatic ductal adenocarcinoma (n = 10) were treated with canakinumab, a high-affinity monoclonal human antiinterleukin-1β (IL1β), the PD1 blocking antibody spartalizumab, and gemcitabine/n(ab)paclitaxel. Analysis of paired peripheral blood from patients in the trial versus patients receiving multiagent chemotherapy showed a modest increase in HLA-DR+CD38+ activated CD8+ T cells and a decrease in circulating monocytic myeloid-derived suppressor cells (MDSC) by flow cytometry for patients in the trial but not in controls. Similarly, we used patient serum to differentiate monocytic MDSCs in vitro and showed that functional inhibition of T-cell proliferation was reduced when using on-treatment serum samples from patients in the trial but not when using serum from patients treated with chemotherapy alone. Within the tumor, we observed few changes in suppressive myeloid-cell populations or activated T cells as assessed by single-cell transcriptional profiling or multiplex immunofluorescence, although increases in CD8+ T cells suggest that improvements in the tumor immune microenvironment might be revealed by a larger study. Overall, the data indicate that exposure to PD1 and IL1β blockade induced a modest reactivation of peripheral CD8+ T cells and decreased circulating monocytic MDSCs; however, these changes did not lead to similarly uniform alterations in the tumor microenvironment.

Introduction. Pseudoangiomatous stromal hyperplasia (PASH) presenting as gigantomastia is rare in pregnancy but can result in severe clinical consequences for both mother and fetus. Case Presentation. A 43-year-old female with a history of biopsy-proven bilateral PASH presented at 22 3/7 weeks gestation with massive bilateral breast enlargement that was symptomatic. After multidisciplinary care, she underwent bilateral mastectomies and delivered at term with no additional complications. Conclusion. Pregnant women who undergo mastectomies for PASH-induced gigantomastia during their second trimesters will likely recover quickly, and fetal risks are low. Given the rarity of this breast entity, management guidelines are sparse. Our case report is an effort to comprehensively review this condition and share the clinical recommendations made by our institutions multidisciplinary team.

Supplemental Figure 3: Presence of canakinumab does not interfere with the ability to detect IL-1b in patient serum. Baseline serum from three randomly selected patients with pancreatic ductal adenocarcinoma was evaluated by cytokine bead array for IL-1b. For each patient sample, canakinumab was spiked in at the indicated concentrations. Note that measured IL-1b values were consistent across all samples from the same patient, regardless of the presence of canakinumab.

Supplemental Figure 5: Addition of TNFa ameliorates myeloid suppression in vitro. (A) Histogram of HLA-DR mean fluorescence intensity of CD33+ SSCA high cells from monocytes cocultured for a week with 75 pg/ML M-CSF with the addition of 10 ng/mL each GM-CSF/ IL-6 or 10ng/mL IL-1b with or without an IL-1b blocking antibody. (B) Induced MoMDSCs from panel A were then cultured with CFSE-labeled T cells for 3 days coculture at a 1:1 ratio, and T cell proliferation was assessed by flow cytometry. Proliferation indices were calculated. (C) MoMDSCs induced from monocytes cultured for 7 days with the indicated cytokines were then cultured with CFSE-labeled T cells for 3 days coculture at a 1:1 ratio, and T cell proliferation was assessed by flow cytometry. Representative histograms are shown. (D) Proliferation indices from the data shown in C were calculated.