BackgroundGastrointestinal cancer patients are susceptible to significant postoperative morbidity. The aim of this systematic review was to examine the effects of preoperative exercise therapy (PET) on patients undergoing surgery for GI malignancies.MethodsIn accordance with PRISMA statement, all prospective clinical trials of PET for patients diagnosed with GI cancer were identified by searching MEDLINE, Embase, Cochrane Library, ProQuest, PROSPERO, and DARE (March 8, 2017). The characteristics and outcomes of each study were extracted and reviewed. Risk of bias was evaluated using the Cochrane risk of bias tool by two independent reviewers.ResultsNine studies (534 total patients) were included in the systematic review. All interventions involved aerobic training but varied in terms of frequency, duration, and intensity. PET was effective in reducing heart rate, as well as increasing oxygen consumption and peak power output. The postoperative course was also improved, as PET was associated with more rapid recovery to baseline functional capacity after surgery.ConclusionsPET for surgical patients with gastrointestinal malignancies may improve physical fitness and aid in postoperative recovery.

Intratumoral T-cell dysfunction is a hallmark of pancreatic tumors, and efforts to improve dendritic cell (DC)-mediated T-cell activation may be critical in treating these immune therapy unresponsive tumors. Recent evidence indicates that mechanisms that induce dysfunction of type 1 conventional DCs (cDC1) in pancreatic adenocarcinomas (PDACs) are drivers of the lack of responsiveness to checkpoint immunotherapy. However, the impact of PDAC on systemic type 2 conventional DC (cDC2) development and function has not been well studied. Herein, we report the analysis of 3 cohorts, totaling 106 samples, of human blood and bone marrow (BM) from PDAC patients for changes in cDCs. We found circulating cDC2s and their progenitors were significantly decreased in the blood of PDAC patients, and repressed numbers of cDC2s were associated with poor prognosis. Serum cytokine analyses identified IL6 as significantly elevated in PDAC patents and negatively correlated with cDC numbers. In vitro, IL6 impaired the differentiation of cDC1s and cDC2s from BM progenitors. Single-cell RNA sequencing analysis of human cDC progenitors in the BM and blood of PDAC patients showed an upregulation of the IL6/STAT3 pathway and a corresponding impairment of antigen processing and presentation. These results suggested that cDC2s were systemically suppressed by inflammatory cytokines, which was linked to impaired antitumor immunity.

Tumor-associated macrophages (TAMs) are abundant in pancreatic ductal adenocarcinomas (PDACs). While TAMs are known to proliferate in cancer tissues, the impact of this on macrophage phenotype and disease progression is poorly understood. We showed that in PDAC, proliferation of TAMs could be driven by colony stimulating factor-1 (CSF1) produced by cancer-associated fibroblasts. CSF1 induced high levels of p21 in macrophages, which regulated both TAM proliferation and phenotype. TAMs in human and mouse PDACs with high levels of p21 had more inflammatory and immunosuppressive phenotypes. p21 expression in TAMs was induced by both stromal interaction and/or chemotherapy treatment. Finally, by modeling p21 expression levels in TAMs, we found that p21-driven macrophage immunosuppression in vivo drove tumor progression. Serendipitously, the same p21-driven pathways that drive tumor progression also drove response to CD40 agonist. These data suggest that stromal or therapy-induced regulation of cell cycle machinery can regulate both macrophage-mediated immune suppression and susceptibility to innate immunotherapy.

FOLFIRINOX is the first line treatment option for patients with pancreatic ductal adenocarcinoma (PDAC). Neoadjuvant chemotherapy has a beneficial effect on overall survival in PDAC in comparison with upfront surgery and adjuvant therapy. However, chemotherapy has not yet been successfully combined with immune therapy in PDAC. Herein, we characterize the immunologic effect of FOLFIRINOX and thus provide a rationale for future combination with immune therapy in PDAC. Peripheral Blood Mononuclear Cells were obtained from treatment-naïve (n=20) and FOLFIRINOX-treated patients (n=15) with primary PDAC tumors. Immune cell subset composition was assessed by using mass cytometry (CyTOF). Response to FOLFIRINOX was defined as a reduction in tumor size by more than 30%. 8 of 15 patients were considered responders with a range from 32 to 60% reduction in tumor volume. Responders to FOLFIRINOX showed a significantly higher proportion of CD8+ T cells and lower proportion of monocytes in their peripheral blood compared to treatment naïve patients (both p<0.05). Responders to FOLFIRINOX treatment also showed a significantly lower percentage of CD39+ Treg cells and a significantly higher percentage of CXCR3+CCR6+ Th1/Th17 cells compared to treatment naïve patients (both p<0.05). Lastly, FOLFIRINOX responders showed significantly higher proportions of Tbet expressing CD4+ and CD8+ T cells compared to non-responder patients (both p<0.05). Taken together, our study reveals that neoadjuvant chemotherapy with FOLFIRINOX could enhance functional T cells and down-regulate suppressor cells in circulation. Thus, combination neoadjuvant FOLFIRINOX chemotherapy with immunotherapy may improve clinical outcome.

Tumor-associated macrophages (TAMs) are involved in many aspects of cancer progression and correlate with poor clinical outcomes in many cancer types, including pancreatic ductal adenocarcinomas (PDACs). Previous studies have shown that TAMs can populate PDAC tumors not only by monocyte recruitment but also by local proliferation. However, the impact local proliferation might have on macrophage phenotype and cancer progression is unknown. Here, we utilized genetically engineered cancer models, single-cell RNA-sequencing data, and in vitro systems to show that proliferation of TAMs was driven by colony stimulating factor-1 (CSF1) produced by cancer-associated fibroblasts. CSF1 induced high levels of p21 in macrophages, which regulated both TAM proliferation and phenotype. TAMs in human and mouse PDACs with high levels of p21 had more inflammatory and immunosuppressive phenotypes. The p21 expression in TAMs was induced by both stromal interaction and/or chemotherapy treatment. Finally, by modeling p21 expression levels in TAMs, we found that p21-driven macrophage immunosuppression in vivo drove tumor progression. Serendipitously, the same p21-driven pathways that drive tumor progression, also drive response to CD40 agonist. These data suggest that stromal or therapy-induced regulation of cell cycle machinery can regulate both macrophage-mediated immune suppression and susceptibility to innate immunotherapy.SummaryTAMs are indicative of poor clinical outcomes and in PDAC their number is sustained in part by local proliferation. This study shows that stromal desmoplasia drives local proliferation of TAMs, and induces their immunosuppressive ability through altering cell cycle machinery, including p21 expression. Serendipitously, these changes in p21 in TAMs also potentially render tumors more sensitive to CD40 agonist therapy.