PD-L1 was expressed in about 50% of the PanNETs analyzed; this frequency is similar to that described by Kim et al
PD-L1 was expressed in about 50% of the PanNETs analyzed; this frequency is similar to that described by Kim et al. cell cytoplasm, in 5 (6%) only on the PanNET cell membrane, and in the remaining 22 (27%) on both the PanNET cell membrane and in the cytoplasm. B7-H3 was expressed in stromal cells of 76 (73%) tumors, with no relationship to its cytoplasmic or cell membrane expression by PanNET cells. There was no association between PD-L1 and B7-H3 expression. Neither PD-L1 nor B7-H3 expression was associated with HLA-A or HLA-B/C expression; however, membranous B7-H3 expression (with or without cytoplasmic expression) was significantly associated with 2m expression (=0.04). values derived from log-rank tests. Table 2. Univariate and multivariate analyses of DFS or DSS with immune parameters and clinicopathologic characteristics in patients with PanNET values derived from logrank tests. On multivariate survival analyses, number of TAMs Rabbit Polyclonal to ATRIP (HR=1.1, 95%CI: 1.04C1.28, em P /em =0.02), WHO grade 2 (HR=2.3, 95%CI: 1.06C5.44, em P /em =0.04), T stage 2 (HR=2.3, 95%CI: 1.29C4.13, em P /em =0.01), and lymph node positivity (HR=2.8, 95%CI: 1.05C7.45, em P /em =0.04) were all independent predictors of DFS (Table 2). Number of TAMs (HR=1.06, 95%CI: 1.01C1.12, P=0.026) and T stage 2 (HR=2.6, 95%CI: 1.2C5.4, P=0.012) continued to be independent predictors of DFS when only WHO grade 1 PanNETs were included in the multivariate analysis. Furthermore, the number of TAMs (HR=1.1, 95%CI: 1.03C1.29, em P /em =0.02) was the sole independent predictor of DSS (Table 2). Discussion To improve our understanding of the role of the immune microenvironment in the clinical course of PanNET, we performed a comprehensive analysis of more than 100 well-annotated PanNETs. Tumor-infiltrating immune cells were identified in all the PanNETs analyzed. CD8+ T cells, CD4+ cells and macrophages were evaluated since they appear to influence DFS and DSS in other cancer types (36C38). PanNET cells appear to avail themselves of several multiple escape mechanisms to avoid destruction by the hosts immune system (Supplementary Table. S6). These include: i) abnormalities in HLA class I expression by PanNET cells, which may result in their defective recognition by cognate T cells, and ii) a defective effector phase of the immune response because of inhibitory signals released by suppressor cells and/or checkpoint molecules in the tumor microenvironment. The number of TAMs was the sole predictor of DSS. A higher number of TAMs, along with WHO grade, T stage, and lymph node positivity were all independent predictors of DFS. When we analyzed only WHO grade I PanNETs, the number of TAMs and T stage continued to be independent predictors of DFS. The above data suggests that the extent of TAM infiltration may allow us to better stratify patients and identify those who have a poor prognosis despite a low WHO grade. In this regard, TAMs have been shown to dampen TA-specific immune responses in PDAC both in mice and in humans (39). This defect may reflect a reduction in the number of tumor-infiltrating CD8+ T cells associated with TAMs cIAP1 Ligand-Linker Conjugates 3 and/or the release of inhibitory signals by molecules such as members of the B7 family (40). An additional mechanism underlying the association of TAM and T cell infiltration with the clinical course of the disease is suggested by the results recently described in a mouse PDAC model (41). T cell infiltration was reactivated both at the epigenetic and at the functional level after TAM elimination, with a switch from IL-10-secreting T cells towards an effector/memory phenotype, as demonstrated by the increased percentage of IFN+ T cells in the tumor microenvironment. This switch could be at least in part mediated by inflammatory cytokines and chemokines secreted in response to trabectedin treatment (42). These results altogether imply that eliminating TAMs may have a beneficial effect on the clinical course of the disease. This possibility cIAP1 Ligand-Linker Conjugates 3 is being tested in a number of clinical trials which utilize chemotherapeutic agents as individual reagents or in combination with checkpoint inhibitors, as recently reviewed by Mantovani et al (43). HLA class I expression, which is required to present TA-derived peptides to cognate T cells, was defective in about 70% of the PanNETs analyzed. This frequency, which is similar to that found by Sato et al cIAP1 Ligand-Linker Conjugates 3 (13) in 16 PanNETs, is at the upper limit of the frequency of HLA class I defects present in many other cancer types (30,44,45). As observed in other cancer types (46,47), HLA class I defects in PanNETs are clinically relevant, since they are associated with a poor.