Spatial heterogeneity of tumor cells and the tissue microenvironment in oral squamous cell carcinoma.

PURPOSE: This study describes the morphologic and phenotypic spatial heterogeneity of tumor cells and the tissue microenvironment (TME), focusing on immune infiltration in OSCCs. STUDY DESIGN: Patients with OSCCs and planned surgical tumor resection were eligible for the study. Two biopsies each from the tumor center and the tumor rim were obtained. Immunohistochemical characterization of tumor and immune cells was performed using a panel of immunohistochemical markers. RESULTS: Thirty-six biopsies were obtained from the 9 patients. All patients showed an individual marker expression profile with ITH. Within the same biopsy, the CPS and TPS scores showed relevant variations in PD-L1 expression. Comparisons between the tumor center and rim revealed significant differences in the up/downregulation of p53. Marker expression of patients with recurrences clustered similarly, with the higher expression of FoxP3, IDO, CD4, CD68, and CD163 at the tumor rim. CONCLUSION: OSCCs were found to exhibit relevant ITH involving both tumor cells and TME, suggesting that biomarker analysis of multiple tumor regions may be helpful for clinical decision making and tumor characterization. The analysis of multiple spots within a biopsy is recommended for a reliable determination of PD-L1 expression and other biomarkers, impacting current clinical assessments.

Favorable prognostic influence of T-box transcription factor Eomesodermin in metastatic renal cell cancer patients.

T-box transcription factors, T-box expressed in T cells (T-bet) encoded by Tbx21 and Eomesodermin (Eomes), drive the differentiation of effector/memory T cell lineages and NK cells. The aim of the study was to determine the prognostic influence of the expression of these transcription factors in peripheral blood (pB) in a cohort of 41 metastatic (m) RCC patients before receiving sorafenib treatment and to analyze their association with the immunophenotype in pB. In contrast to Tbx21, in the multivariate analysis including clinical features, Eomes mRNA expression was identified as an independent good prognostic factor for progression-free survival (PFS, p = 0.042) and overall survival (OS, p = 0.001) in addition to a favorable ECOG performance status (p = 0.01 and p = 0.008, respectively). Eomes expression correlated positively not only with expression of Tbx21 and TGFß1 mRNA, but also with mRNA expression of the activation marker ICOS, and with in vivo activated HLA-DR(+) T cells. Eomes expression was negatively associated with TNFα-producing T cells. On protein level, Eomes was mainly expressed by CD56(+)CD3(-) NK cells in pB. In conclusion, we identified a higher Eomes mRNA expression as an independent good prognostic factor for OS and PFS in mRCC patients treated with sorafenib.

Dendritic cells coordinate innate immunity via MyD88 signaling to control Listeria monocytogenes infection.

Listeria monocytogenes (LM), a facultative intracellular Gram-positive pathogen, can cause life-threatening infections in humans. In mice, the signaling cascade downstream of the myeloid differentiation factor 88 (MyD88) is essential for proper innate immune activation against LM, as MyD88-deficient mice succumb early to infection. Here, we show that MyD88 signaling in dendritic cells (DCs) is sufficient to mediate the protective innate response, including the production of proinflammatory cytokines, neutrophil infiltration, bacterial clearance, and full protection from lethal infection. We also demonstrate that MyD88 signaling by DCs controls the infection rates of CD8α(+) cDCs and thus limits the spread of LM to the T cell areas. Furthermore, in mice expressing MyD88 in DCs, inflammatory monocytes, which are required for bacterial clearance, are activated independently of intrinsic MyD88 signaling. In conclusion, CD11c(+) conventional DCs critically integrate pathogen-derived signals via MyD88 signaling during early infection with LM in vivo.