Phenotypic immune characterization of gastric and esophageal adenocarcinomas reveals profound immune suppression in esophageal tumor locations.

Background: Tumors in the distal esophagus (EAC), gastro-esophageal junction including cardia (GEJAC), and stomach (GAC) develop in close proximity and show strong similarities on a molecular and cellular level. However, recent clinical data showed that the effectiveness of chemo-immunotherapy is limited to a subset of GEAC patients and that EACs and GEJACs generally benefit less from checkpoint inhibition compared to GACs. As the composition of the tumor immune microenvironment drives response to (immuno)therapy we here performed a detailed immune analysis of a large series of GEACs to facilitate the development of a more individualized immunomodulatory strategy. Methods: Extensive immunophenotyping was performed by 14-color flow cytometry in a prospective study to detail the immune composition of untreated gastro-esophageal cancers (n=104) using fresh tumor biopsies of 35 EACs, 38 GEJACs and 31 GACs. The immune cell composition of GEACs was characterized and correlated with clinicopathologic features such as tumor location, MSI and HER2 status. The spatial immune architecture of a subset of tumors (n=30) was evaluated using multiplex immunohistochemistry (mIHC) which allowed us to determine the tumor infiltration status of CD3+, CD8+, FoxP3+, CD163+ and Ki67+ cells. Results: Immunophenotyping revealed that the tumor immune microenvironment of GEACs is heterogeneous and that immune suppressive cell populations such as monocytic myeloid-derived suppressor cells (mMDSC) are more abundant in EACs compared to GACs (p<0.001). In contrast, GACs indicated a proinflammatory microenvironment with elevated frequencies of proliferating (Ki67+) CD4 Th cells (p<0.001), Ki67+ CD8 T cells (p=0.002), and CD8 effector memory-T cells (p=0.024). Differences between EACs and GACs were confirmed by mIHC analyses showing lower densities of tumor- and stroma-infiltrating Ki67+ CD8 T cells in EAC compared to GAC (both p=0.021). Discussions: This comprehensive immune phenotype study of a large series of untreated GEACs, identified that tumors with an esophageal tumor location have more immune suppressive features compared to tumors in the gastro-esophageal junction or stomach which might explain the location-specific responses to checkpoint inhibitors in this disease. These findings provide an important rationale for stratification according to tumor location in clinical studies and the development of location-dependent immunomodulatory treatment approaches.

Course of Disease and Clinical Outcome of Infective Endocarditis in HIV-infected Individuals: A Systematic Review and Meta-analysis.

Infective endocarditis (IE) causes substantial morbidity and mortality if untreated. The clinical course of IE might be different in HIV-positive patients as a result of immune dysfunction. This systematic review investigates the clinical course of IE in HIV-positive compared to HIV-negative patients. A systematic search was performed in PubMed, EMBASE, and Cochrane Library and registered in PROSPERO (CRD42016048649). All articles from 1996 and onward addressing the clinical outcome of HIV-positive adults suffering from IE were reviewed and included based on predefined inclusion and exclusion criteria. A meta-analysis was performed for the outcome mortality. Twenty-three articles were included of which eight included HIVpositive patients only, and 15 compared HIV-positive to HIV-negative patients. Two studies included patients on antiretroviral therapy (ART). HIV and intravenous drug use (IVDU) were closely related. Mortality was higher in HIV-positive patients with a CD4 count below 200 cells/µl than in HIV-positive patients with a higher CD4 count, while mortality was similar for HIV-positive compared to HIV-negative patients (risk ratio = 0.86 [95% confidence interval: 0.53-1.40]). No difference was found in length of hospital stay or rehospitalization. Clinical outcomes were strongly related to the right- or left-sided endocarditis. The clinical course of IE is not different for patients with and without HIV. Clinical outcomes were mainly associated with other factors, such as IVDU and side of cardiac involvement, rather than HIV status.