Intrahepatic immune infiltrate in chronic hepatitis B and chronic hepatitis C: Similar but not the same.

In chronic hepatitis B (CHB) and C (CHC) infections, the composition of the immune cell microenvironment at the site of infection is poorly understood. Thus, our aim was to characterize and compare liver infiltrates to identify shared and exclusive hepatic immune components. Immunohistochemistry was performed on 26 CHB and 42 CHC liver biopsies to determine Th (CD4+), Th1 (T-bet+), Th17 (IL-17A+), Treg (Foxp3+) and CTL (CD8+) cells frequency in portal/periportal and intralobular areas and relate them to liver damage. CHB and CHC cases shared a portal/periportal CD4+ lymphocyte predominance and a lobular CD8+ lymphocyte majority. However, CHC exhibited a concomitant lobular T-bet+ cell dominance while in CHB FoxP3+ cells prevail. CHC disclosed higher frequencies of P/P FoxP3+, IL-17A+ and T-bet+ cells and intralobular CD4+, IL-17A+ and T-bet+ lymphocytes. HBeAg+ chronic hepatitis and CHC cell frequencies were similar except for lobular T-bet+ that remained higher among CHC cases. Comparison among cases with less severe liver disease revealed lower lymphocyte frequencies in CHB samples, while no differences were observed between patients with more severe stages. Interestingly, in CHB portal/periportal CD4+ and lobular CD4+, CD8+ and IL-17A+ cells were associated with severe hepatitis. Even when all studied populations were identified in both infections preferential lymphocyte frequencies and prevalence at different areas along with their association with liver damage highlighted that CHB and CHC immune responses are not the same.

A high CD8 to FOXP3 ratio in the tumor stroma and expression of PTEN in tumor cells are associated with improved survival in non-metastatic triple-negative breast carcinoma.

BACKGROUND: Triple-negative mammary carcinoma (TNBC) is an aggressive breast cancer subtype associated with dismal prognosis. The interaction between the immune system and the cancer cells plays a crucial role in tumor development and progression. However, it is still unclear how each diverse cell of the immune system contributes to the prognosis of patients with breast cancer. In this study, we investigated how the cell composition of the immune cell infiltrated modifies the survival of patients with resected TNBC. METHODS: Retrospectively, we collected data from 76 patients diagnosed with non-metastatic TNBC with available tissue blocks for tissue micro-array (TMA) construction. The TMA was constructed using two cores from each tumor block. The expression of CD4, CD8, FOXP3, CD20, CD68, CD163, PD-1, PD-L1, PTEN and phospho-STAT1 was determined by immunohistochemistry. RESULTS: We observed that the inflammatory infiltrate in TNBC is enriched for M2 macrophages and T lymphocytes (CD4+, CD8+). PD-L1 expression in the stroma was associated with the percentage of TILs (p = 0.018) as, PD-L1 expression in the tumor was associated with the percentage of TILs (p = 0.049). We found a correlation between TILs and PD-L1 expression in stroma cells (p = 0.020) and in tumor cells (p = 0.027). In our cohort, we observed a trend for improved survival associated with higher CD8+ (p = 0.054) and CD4 + (p = 0.082) cell counts, but the results were not statistically significant. Conversely, the expression of PTEN in tumor cells and a low number of FOXP3+ cells in tumor stroma were both associated with improved OS. The CD8 to FOXP3 ratio and the CD4 to FOXP3 ratio were associated with better OS as well, however, only the CD8 to FOXP3 ratio had its prognostic impact confirmed in the METABRIC TNBC cohort. There was no association between PD-L1 expression and OS. CONCLUSION: TNBC tumor microenvironment is enriched for lymphocytes and macrophages. FOXP3 expression and the CD8 to FOXP3 ratio in the tumor stroma as well as the loss of PTEN expression in tumor cells are prognostic factors in non-metastatic TNBC.

Immune Checkpoints Pathways in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors usually diagnosed at an advanced stage and characterized by a poor prognosis. The main risk factors associated with its development include tobacco and alcohol consumption and Human Papillomavirus (HPV) infections. The immune system has a significant role in the oncogenesis and evolution of this cancer type. Notably, the immunosuppressive tumor microenvironment triggers immune escape through several mechanisms. The improved understanding of the antitumor immune response in solid tumors and the role of the immune checkpoint molecules and other immune regulators have led to the development of novel therapeutic strategies that revolutionized the clinical management of HNSCC. However, the limited overall response rate to immunotherapy urges identifying predictive biomarkers of response and resistance to treatment. Here, we review the role of the immune system and immune checkpoint pathways in HNSCC, the most relevant clinical findings linked to immunotherapeutic strategies and predictive biomarkers of response and future treatment perspectives.

Aberrant expression of RSK1 characterizes high-grade gliomas with immune infiltration.

The p90 ribosomal S6 kinase (RSK) family, a downstream target of Ras/extracellular signal-regulated kinase signaling, can mediate cross-talk with the mammalian target of rapamycin complex 1 pathway. As RSK connects two oncogenic pathways in gliomas, we investigated the protein levels of the RSK isoforms RSK1-4 in nontumoral brain (NB) and grade I-IV gliomas. When compared to NB or low-grade gliomas (LGG), a group of glioblastomas (GBMs) that excluded long-survivor cases expressed higher levels of RSK1 (RSK1hi ). No difference was observed in RSK2 median-expression levels among NB and gliomas; however, high levels of RSK2 in GBM (RSK2hi ) were associated with worse survival. RSK4 expression was not detected in any brain tissues, whereas RSK3 expression was very low, with GBM demonstrating the lowest RSK3 protein levels. RSK1hi and, to a lesser extent, RSK2hi GBMs showed higher levels of phosphorylated RSK, which reveals RSK activation. Transcriptome analysis indicated that most RSK1hi GBMs belonged to the mesenchymal subtype, and RSK1 expression strongly correlated with gene expression signature of immune infiltrates, in particular of activated natural killer cells and M2 macrophages. In an independent cohort, we confirmed that RSK1hi GBMs exclude long survivors, and RSK1 expression was associated with high protein levels of the mesenchymal subtype marker lysosomal protein transmembrane 5, as well as with high expression of CD68, which indicated the presence of infiltrating immune cells. An RSK1 signature was obtained based on differentially expressed mRNAs and validated in public glioma datasets. Enrichment of RSK1 signature followed glioma progression, recapitulating RSK1 protein expression, and was associated with worse survival not only in GBM but also in LGG. In conclusion, both RSK1 and RSK2 associate with glioma malignity, but displaying isoform-specific peculiarities. The progression-dependent expression and association with immune infiltration suggest RSK1 as a potential progression marker and therapeutic target for gliomas.

Immune cell infiltration in Ectomesenchymal chondromyxoid tumor: An immunohistochemical study.

Ectomesenchymal chondromyxoid tumor (ECT) is a rare benign neoplasm, often affecting the anterior dorsum of the tongue. To date, approximately 74 cases of lingual ECT have been published. This report describes, for the first time, the morphological and immunohistochemical features of a unique ECT case, which revealed diffuse infiltration by immune cells with a dendritic-like appearance inside the tumor proliferation. The significance of these findings and discussion about the tumor cell-immune cell interactions are presented.