Michael J. Cavnar

Tumor-associated macrophages (TAMs) are a major component of the cancer microenvironment. Modulation of TAMs is under intense investigation because they are thought to be nearly always of the M2 subtype, which supports tumor growth. Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and typically results from an activating mutation in the KIT oncogene. Using a spontaneous mouse model of GIST and 57 freshly procured human GISTs, we discovered that TAMs displayed an M1-like phenotype and function at baseline. In both mice and humans, the KIT oncoprotein inhibitor imatinib polarized TAMs to become M2-like, a process which involved TAM interaction with apoptotic tumor cells leading to the induction of CCAAT/enhancer binding protein (C/EBP) transcription factors. In human GISTs that eventually developed resistance to imatinib, TAMs reverted to an M1-like phenotype and had a similar gene expression profile as TAMs from untreated human GISTs. Therefore, TAM polarization depends on tumor cell oncogene activity and has important implications for immunotherapeutic strategies in human cancers.

Objective: To characterize the results of surgery for gastrointestinal stromal tumor (GIST) in the pre and post-imatinib eras at a single institution and to identify current prognostic clinicopathologic factors. Background: Imatinib has radically changed the management of GIST, yet the magnitude of impact on outcome across the spectrum of GIST presentation and relevance of historical prognostic factors are not well defined. Methods: We retrospectively analyzed 1000 patients who underwent surgery for GIST at our institution from 1982 to 2016. Patients were stratified by presentation status as primary tumor only (PRIM), primary with synchronous metastasis (PRIM + MET), or metachronous recurrence/metastases (MET), and also imatinib era (before and after it became available). Cox proportional-hazard models and Kaplan-Meier methods were used to model and estimate overall survival (OS) and recurrence-free survival (RFS). Results: OS was longer in the imatinib era compared with the pre-imatinib era in each presentation group, including in Miettinen high-risk primary tumors. Among PRIM patients from the pre-imatinib era, tumor site, size, and mitotic rate were independently associated with OS and RFS on multivariate analysis. PRIM patients in the imatinib era who received imatinib (neoadjuvant and/or adjuvant) had higher risk tumors, but after adjusting for treatment, only size >10 cm remained independently prognostic of RFS [hazard ratio (HR) 3.85, 95% confidence interval (CI) 2.00–7.40, P < 0.0001) and OS (HR 3.37, 95% CI 1.60–7.13, P = 0.001)]. Conclusions: Patients treated in the imatinib era had prolonged OS across all presentations. In the imatinib era, among site, size, and mitotic rate, high-risk features were associated with treatment with the drug, but only size >10 cm correlated with outcome. Imatinib should still be prescribed for patients with high-risk features.

Septic peritonitis remains a major cause of death. Neutrophils and inflammatory monocytes are principal components of the innate immune system and are essential for defense against a range of microbial pathogens. Their role and interaction in polymicrobial sepsis have not been defined clearly. Using a murine model of CLP to induce moderate sepsis, we found that neutrophil depletion did not alter survival, whereas depletion of neutrophils and inflammatory monocytes markedly reduced survival. After neutrophil depletion, inflammatory monocytes had greater phagocytic capacity and oxidative burst, and increased expression of costimulatory molecules, TNF, and iNOS. Notably, peritoneal neutrophils produced IL-10 following CLP. Adoptive i.p. transfer of WT but not IL-10(-/-) neutrophils into septic mice reduced monocyte expression of TNF. In vitro experiments confirmed that monocyte suppression was mediated by neutrophil-derived IL-10. Thus, during septic peritonitis, neutrophils suppress peritoneal inflammatory monocytes through IL-10 and are dispensable for survival.