Tumor-associated macrophages (TAMs) as immune cells within the tumor microenvironment have gained much interests as basic science regarding their roles in tumor progression unfolds. Better understanding of their polarization into pro-tumoral phenotype to promote tumor growth, tumor angiogenesis, immune evasion, and tumor metastasis has prompted various studies to investigate their clinical significance as a biomarker of predictive and prognostic value across different cancer types. Yet, the methodologies to investigate the polarization phenomena in solid tumor tissue vary. Nonetheless, quantifying the ratio of M1 to M2 TAMs has emerged to be a prevailing parameter to evaluate this polarization phenomena for clinical application. This mini-review focuses on recent studies exploring clinical significance of M1/M2 TAM ratio in human cancer tissue and critically evaluates the technicalities and challenges in quantifying this parameter for routine clinical practice. Immunohistochemistry appears to be the preferred methodology for M1/M2 TAM evaluation as it is readily available in clinical laboratories, albeit with certain limitations. Recommendations are made to standardize the quantification of TAMs for better transition into clinical practice and for better comparison among studies in various populations of patients and cancer types.

Semaphorins are a family of phylogenetically conserved soluble and transmembrane proteins. Although many soluble semaphorins deliver guidance cues to migrating axons during neuronal development, some members are involved in immune responses. For example, CD100 (also known as Sema4D), a class IV transmembrane semaphorin, signals through CD72 to effect nonredundant roles in immune responses in a ligand-receptor system that is distinct from any seen previously in the nervous system. Here we report that the class IV semaphorin Sema4A, which is expressed in dendritic cells and B cells, enhances the in vitro activation and differentiation of T cells and the in vivo generation of antigen-specific T cells. Treating mice with monoclonal antibodies against Sema4A blocks the development of an experimental autoimmune encephalomyelitis that is induced by an antigenic peptide derived from myelin oligodendrocyte glycoprotein. In addition, expression cloning shows that the Sema4A receptor is Tim-2, a member of the family of T-cell immunoglobulin domain and mucin domain (Tim) proteins that is expressed on activated T cells.

Sema4D, also known as CD100, is a protein belonging to class IV semaphorin. Its physiologic roles in the immune and nervous systems have been extensively explored. However, the roles of Sema4D have extended beyond these traditionally studied territories. Via interaction with its high affinity receptor Plexin-B1, Sema4D-Plexin-B1 involvement in tumor progression is strongly implied. Here, we critically review and delineate the Sema4D-Plexin-B1 interaction in many facets of tumor progression: tumor angiogenesis, regulation of tumor-associated macrophages and control of invasive growth. We correlate the in vitro and in vivo experimental data with the clinical study outcomes, and present a molecular mechanistic basis accounting for the intriguingly contradicting results from these recent studies.

BACKGROUND. CD100, a class IV semaphorin, promotes angiogenesis, invasive growth, proliferation, and antiapoptosis of cancer cells in vitro. The expression of CD100 in soft tissue sarcoma (STS) and its correlation with clinicopathologic factors and prognostic significance were evaluated. METHODS. Expression levels of CD100 in patients with localized STS were evaluated immunohistochemically on paraffin‐embedded sections from 81 patients, including 47 men and 34 women with a median age of 54 years. Staining intensity was categorized into weaker than (level 1) or equal to that of lymphocytes with a rate of <10% stained tumor cells (level 2) or >10% stained tumor cells (level 3). Ki‐67 staining was performed in parallel. RESULTS. Forty‐two tumors (52%) had level 1 CD100 expression, 18 tumors (22%) had level 2 CD100 expression, and 21 tumors (26%) had level 3 CD100 expression. Tumors that had level 2 and 3 CD100 expression were correlated significantly with higher mitotic count, cellularity, ratio of necrosis, and Ki‐67 labeling index (LI) compared with tumors that had level 1 CD100 expression. There was no correlation between CD100 expression and other characteristics. Among the 3 levels of CD100 expression, higher expression levels were correlated with poorer overall and disease‐free survival. Multivariate analysis revealed that CD100 expression (levels 1 and 2 vs level 3) and tumor size (≤5 cm vs >5 cm) were independent prognosticators for overall survival (P < .05 for both), and CD100 expression (levels 1 and 2 vs level 3) was an independent prognosticator for disease‐free survival (P < .05). CONCLUSIONS. The results from this study indicated the demonstrated prognostic significance of CD100 expression in STS. Cancer 2007. © 2007 American Cancer Society.

TRPM4 protein expression is up-regulated in DLBCL cases compared to non-malignant B cells with preferential expression in ABC-DLBCL cases, and it confers significantly poorer DLBCL patient outcomes.

Tumor-associated macrophages play a crucial role in breast cancer progression and tumor angiogenesis. However, evaluation of tumor-associated macrophages incorporating their histological locations is lacking. The aim of this study was to clarify whether macrophages in tumor stroma and macrophages in tumor cell nests have distinctive properties in relation to pertinent breast cancer clinicopathological parameters and tumor angiogenesis. In 94 human invasive breast ductal carcinomas, tumor-associated macrophages were immunostained with anti-CD68 antibody and counted or graded according to these histological locations. Microvessels were immunostained with anti-CD34 antibody and counted for microvessel density. We found that the presence of tumor stromal and tumor nest macrophages was closely correlated (p = 0.001). Both tumor stromal and tumor nest macrophages were associated with mitotic count (p = 0.001 and p = 0.037, respectively). However, only higher tumor stromal macrophage grades were associated with higher tumor grades (p = 0.004) and negative estrogen receptor status (p = 0.007). Multivariate analysis showed that tumors with a high mitotic count score (score 3 vs. scores 1 and 2) had a higher tumor stromal macrophage density (Grades III and IV) when adjusted for tumor size, tubule formation, and estrogen receptor status (odds ratio 3.41, p = 0.010). The tumor nest macrophage count significantly correlated with the microvessel density (p < 0.001). These results imply that tumor stromal macrophages and tumor nest macrophages residing in different tumor microenvironments have distinctive roles.

Background Chikungunya virus (CHIKV) causes febrile illnesses and has always been misdiagnosed as other viral infections, such as dengue and Zika; thus, a laboratory test is needed. Serological tests are commonly used to diagnose CHIKV infection, but their accuracy is questionable due to varying degrees of reported sensitivities and specificities. Herein, we conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of serological tests currently available for CHIKV. Methodology and principal findings A literature search was performed in PubMed, CINAHL Complete, and Scopus databases from the 1st December 2020 until 22nd April 2021. Studies reporting sensitivity and specificity of serological tests against CHIKV that used whole blood, serum, or plasma were included. QUADAS-2 tool was used to assess the risk of bias and applicability, while R software was used for statistical analyses. Thirty-five studies were included in this meta-analysis; 72 index test data were extracted and analysed. Rapid and ELISA-based antigen tests had a pooled sensitivity of 85.8% and 82.2%, respectively, and a pooled specificity of 96.1% and 96.0%, respectively. According to our meta-analysis, antigen detection tests serve as a good diagnostic test for acute-phase samples. The IgM detection tests had more than 90% diagnostic accuracy for ELISA-based tests, immunofluorescence assays, in-house developed tests, and samples collected after seven days of symptom onset. Conversely, low sensitivity was found for the IgM rapid test (42.3%), commercial test (78.6%), and for samples collected less than seven of symptom onset (26.2%). Although IgM antibodies start to develop on day 2 of CHIKV infection, our meta-analysis revealed that the IgM detection test is not recommended for acute-phase samples. The diagnostic performance of the IgG detection tests was more than 93% regardless of the test formats and whether the test was commercially available or developed in-house. The use of samples collected after seven days of symptom onset for the IgG detection test suggests that IgG antibodies can be detected in the convalescent-phase samples. Additionally, we evaluated commercial IgM and IgG tests for CHIKV and found that ELISA-based and IFA commercial tests manufactured by Euroimmun (Lübeck, Germany), Abcam (Cambridge, UK), and Inbios (Seattle, WA) had diagnostic accuracy of above 90%, which was similar to the manufacturers’ claim. Conclusion Based on our meta-analysis, antigen or antibody-based serological tests can be used to diagnose CHIKV reliably, depending on the time of sample collection. The antigen detection tests serve as a good diagnostic test for samples collected during the acute phase (≤7 days post symptom onset) of CHIKV infection. Likewise, IgM and IgG detection tests can be used for samples collected in the convalescent phase (>7 days post symptom onset). In correlation to the clinical presentation of the patients, the combination of the IgM and IgG tests can differentiate recent and past infections.

Our findings suggest that treatment with MSCs alone attenuated airway inflammation and structural changes of the airway. Treatment with MSC-pANGPT1 provided an additional effect in reducing the expression levels of various pro-inflammatory genes. Both of these treatment enhancing airway repair and therefore may provide a basis for the development of an innovative approach for the treatment and prevention of airway inflammatory diseases.