Prognostic Significance of Tumor-Associated Inflammation in Renal Cell Carcinoma.

This study analyzed tumor-associated inflammation by assessing the expression of cyclophilin A (CypA) and TNF in samples of kidney tumors of various histological types. It was shown that different histological types of renal cell carcinoma differed by the expression of these proteins. Thus, the highest expression of CypA and TNF was observed in papillary and chromophobe kidney cancer, although no correlation with overall bacterial load was found for these tumors. In the case of clear cell renal cell carcinoma, the expression of proinflammatory factors was observed in only half of the cases and directly correlated with the presence of resident bacteria, serving as a favorable prognostic factor for the disease.

Soluble B7-H3 in Colorectal Cancer.

We present the results of comparative ELISA of the concentration of soluble form of immunity checkpoint B7-H3 (sB7-H3) in the serum of patients with colorectal cancer (CRC) at different stages before treatment and healthy control donors. The analysis revealed a statistically significant difference between the median levels of sB7-H3 in the blood serum of CRC patients (19.66 ng/ml) and healthy donors (16.76 ng/ml) (p=0.0025). ROC analysis showed 62.9% sensitivity and 56.7% specificity for CRC patients (cut-off 17.62 ng/ml; p=0.0028). An association of sB7-H3 levels with tumor progression was revealed. We demonstrated that sB7-H3 levels were significantly lower in patients with regional metastases than in patients without metastases (p=0.039) and that sB7-H3 concentration tends to decrease at the late stages of the disease. Thus, high serum level of sB7-H3 in CRC patients can be a favorable prognostic factor in future.

Clinical Significance of CD66b Expression in Non-Small Cell Lung Cancer.

We studied the expression of CD66b (a protein of the cancer-embryonic antigen family, expressed mainly in neutrophils) in tumor and stromal cells of non-small cell lung cancer (93 samples). The number of CD66b+ neutrophils is not associated with clinical and morphological parameters of the tumors and the disease prognosis. However, CD66b is expressed in the tumor cells of most studied samples. CD66b expression is also associated with the histological type of tumor and its localization. Increased expression of CD66b in tumor cells indicated a more favorable prognosis, which allows using this protein as a prognostic marker and as a potential target for the immunotherapy.

Cytotoxic Activity of Macrophages as a Tumor Malignancy Factor.

An experimental cell-based model was developed to study antibody-independent cytotoxic activity of macrophages that allows selection of derivative tumor cells resistant to this activity and clarification of the mechanisms responsible for this selection. Cytotoxic macrophages showing antibody-independent cytotoxic activity were obtained. Derivatives of PC3 and H1299 cells resistant to cytotoxic macrophage activity were generated. The main characteristics of the obtained derivative cells were studied. The proposed experimental model can be used as a tool for studying the mechanisms of the development of tumor cells resistance to antibody-independent cytotoxic activity of macrophages.

Diagnostic and prognostic potential of the resident non-small cell lung cancer microbiome.

The data of a comprehensive comparative study of the taxonomic composition of the resident microbiome of tumors from 26 patients with non-small cell lung cancer are presented. Analysis of taxonomic diversity revealed 10 types, 280 genera and 788 species of microorganisms. The analysis of the relative content and prognostic significance was carried out for 62 dominant genera. Differences in the relative abundance of bacteria of the genera Acinetobacter, Halomonas, and Chryseobacterium between tumor and conditionally normal lung tissue were found, but their diagnostic potential was not confirmed. The correlation analysis did not reveal any relationship between the content of various genera of bacteria and the histological type of the tumor, its localization, and the age of the patients. Differences were found in the content of the studied bacteria depending on the stage of the disease, the presence of regional metastases and tumor differentiation. The prognostic significance of bacteria of the genera Variovorax and Pseudoclavibacter in non-small cell lung cancer was established. The results obtained can be used in the development of new effective methods for the diagnosis and prognosis of non-small cell lung cancer.

Transcriptome of Lung Cancer Cells Resistant to the Cytotoxic Activity of Macrophages.

The role of the immune system in tumor progression has been the subject of research for more than 100 years since Paul Ehrlich hypothesized that the presence of the immune system limits the occurrence of cancer. One of the mechanisms hindering the initiation and progression of the tumor is the cytotoxic activity of macrophages; however, in some cases, it is not sufficient to control tumorigenesis. This may be due to both the development of resistance of tumor cells to the antitumor activity of macrophages and the development of a tolerant phenotype of macrophages that do not have sufficient antitumor activity. In this work, the lung cancer cells resistant to the cytotoxic action of macrophages were obtained and characterized for the first time, and the genes associated with the observed changes were identified. Understanding the mechanisms of resistance of tumor cells to the cytotoxic activity of macrophages and the peculiarities of its manifestation in a tumor environment is critically important for improving the effectiveness of the existing methods of cancer treatment and developing novel methods for tumor immunotherapy.

Comprehensive Analysis of Stromal and Serum Markers in Gastric Cancer.

A comprehensive analysis of the cell phenotype of the inflammatory infiltrate of the tumor stroma represents a promising area of molecular oncology. The study of not only soluble forms of various immunoregulatory molecules, but also their membrane-bound forms is also considered highly relevant. We performed a comprehensive analysis of tissue and circulating forms of the PD-1 and PD-L1 proteins, as well as macrophage and B-cell markers in the tumor stroma of gastric cancer, to assess their clinical and prognostic significance. The tumor and blood plasma samples from 63 gastric cancer patients were studied using ELISA and immunohistochemistry. Malignant gastric tumors were shown to be strongly infiltrated by B-cells, and their number was comparable to that of macrophages. For PU.1 expression, an association with tumor size was observed; i.e., larger tumors were characterized by fewer PU.1+ infiltrating cells (p = 0.005). No clinical significance was found for CD20 and CD163, but their numbers were higher at earlier stages of the disease and in the absence of metastases. It was also demonstrated that the PD-L1 content in tumor cells was not associated with the clinical and morphological characteristics of GC. At the same time, PD-L1 expression in tumor stromal cells was associated with the presence of distant metastases. The analysis of the prognostic significance of all the markers studied demonstrated that CD163 was statistically significantly associated with a poor prognosis for the disease (p = 0.019). In addition, PD-L1 expression in tumor cells tended to indicate a favorable prognosis (p = 0.122). The results obtained in this work indicate that the study of soluble and tissue markers of tumor stroma is promising in prognosticating the course of GC. The search for combinations of markers seems to be highly promising, with their comprehensive analysis capable of helping personalize advanced antitumor therapy.

Soluble B7-H3 in Ovarian Cancer and Its Predictive Value.

The content of the soluble form of protein of the key point of immunity B7-H3 (sB7-H3) in the blood plasma of 75 patients with epithelial ovarian cancer before treatment was measured by ELISA. It is known that B7-H3 belongs to the immunoglobulin superfamily (B7 molecule family) and is involved in the regulation of the immune response mediated by T cells. The sB7-H3 concentration correlated with the clinical and morphological parameters of ovarian cancer. The content of sB7-H3 was higher at the later stages of the disease, in the presence of ascites, and in patients with poorly differentiated ovarian cancer. It was revealed that increased plasma content of sB7-H3 in patients with epithelial ovarian cancer is associated with unfavorable prognosis of the disease. Therefore, sB7-H3 can be used as a prognostic marker in ovarian cancer patients.

Clinical and prognostic significance of the soluble form of the VISTA immunity control point in patients with primary bone tumors.

The data of a comparative enzyme-linked immunosorbent assay of the content of the soluble form of the immunity checkpoint VISTA in the blood serum of 30 healthy donors (control group), 79 patients with primary malignant (osteosarcoma - 30, chondrosarcoma - 31, chordoma - 14) and 14 borderline (giant cell tumor) bone neoplasms are presented. In the general group of patients with malignant neoplasms of bones, the median sVISTA content in blood serum is statistically significant lower than in the control (p = 0.040). In patients with bone tumors and healthy donors over 18 years of age, there was a decrease with age in serum sVISTA levels. There were no significant differences in sVISTA concentration between patients with osteosarcoma, chondrosarcoma and healthy donors. Only in patients with chordoma were sVISTA levels statistically significant lower than in controls (p = 0.013). In the groups of patients with chondrosarcoma and osteosarcoma of the bone, there were no significant associations between the serum sVISTA content and the main clinical and morphological characteristics of the disease. In patients with osteosarcoma, no relationship was found between sVISTA levels and overall survival rates, while in patients with bone chondrosarcoma, there was a tendency towards a favorable prognosis with a high content of the marker in the blood serum.

Immunosuppression Factors PD-1, PD-L1, and IDO1 and Colorectal Cancer.

Due to the low efficiency of immunotherapy for colorectal cancer (CRC), it is extremely promising and relevant to study the mechanisms of immunosuppression. In this work, a comprehensive study of the expression of soluble and tissue forms of PD-1 and PD-L1 in blood serum and tumors of patients with CRC, as well as IDO1 in tumors was performed for the first time. The diagnostic and prognostic significance of the studied parameters was determined. A statistically significant decrease in the number of soluble forms of PD-1 and PD-L1 in the blood serum and the association of the number of PD-L1+ cells in the stroma of tumors with the CRC stage were established. The absence of correlations between soluble and tissue forms of the studied proteins was shown, indicating the presence of independent mechanisms of immunosuppression in CRC, which may explain the ineffectiveness of immunotherapy for this type of tumor.

Expression of Transcription Factor PU.1 in Stromal Cells as a Prognostic Marker in Non-Small Cell Lung Cancer.

Transcription factor PU.1 is involved in hematopoiesis and is expressed in various cells of the inflammatory infiltrate of the tumor stroma, mainly in macrophages. The expression of PU.1 in 100 samples of non-small cell lung cancer was analyzed by the immunohistochemical method. The number of PU.1+ cells did not correlate with clinical and morphological parameters of the tumors. However, increased number of PU.1+ cells significantly correlated with favorable prognosis in adenocarcinoma and poor prognosis in squamous cell carcinoma. Thus, transcription factor PU.1 can serve as a stromal prognostic marker of non-small cell lung cancer depending on the histological type of the tumor.

Soluble forms of immune checkpoints in ovarian cancer.

The data of a complex immunoassay comparative study of the content of soluble forms of sPD-1, sPD-L1, sNKG2D, sNKG2DL1, sB7-H3 and sHLA-G in the blood plasma of 75 patients with epithelial ovarian cancer and 20 healthy donors of the control group are presented. The diagnostic significance of the studied proteins was determined. The study showed that the profile of soluble immunity checkpoints differs when malignant ovarian pathology occurs. There was a statistically significant decrease in the content of sPD-L1, sNKG2DL1, sB7-H3, and sHLA-G in the blood plasma of patients compared with the control group. Differences were found in the content of the studied markers depending on the histological type of tumors. Correlations between the soluble forms of some of the studied proteins are shown, indicating the presence of independent mechanisms of immune regulation in ovarian cancer, which may explain the insufficient effectiveness of the existing immunotherapy for this type of tumor. The results obtained will undoubtedly facilitate the development of new effective methods for the diagnostics and therapy of ovarian cancer.

Smoking-related DNA adducts as potential diagnostic markers of lung cancer: new perspectives.

In recent years, the new direction such as identification of informative circulating markers reflecting molecular genetic changes in the DNA of tumor cells was actively developed. Smoking-related DNA adducts are very promising research area, since they indicate high pathogenetic importance in the lung carcinogenesis and can be identified in biological samples with high accuracy and reliability using highly sensitive mass spectrometry methods (TOF/TOF, TOF/MS, MS/MS). The appearance of DNA adducts in blood or tissues is the result of the interaction of carcinogenic factors, such as tobacco constituents, and the body reaction which is determined by individual characteristics of metabolic and repair systems. So, DNA adducts may be considered as a cumulative mirror of heterogeneous response of different individuals to smoking carcinogens, which finally could determine the risk for lung cancer. This review is devoted to analysis of the role of DNA adducts in lung carcinogenesis in order to demonstrate their usefulness as cancer associated markers. Currently, there are some serious limitations impeding the widespread use of DNA adducts as cancer biomarkers, due to failure of standardization of mass spectrometry analysis in order to correctly measure the adduct level in each individual. However, it is known that all DNA adducts are immunogenic, their accumulation over some threshold concentration leads to the appearance of long-living autoantibodies. Thus, detection of an informative pattern of autoantibodies against DNA adducts using innovative multiplex ELISA immunoassay may be a promising approach to find lung cancer at an early stage in high-risk groups (smokers, manufacturing workers, urban dwellers).

[Interaction of native and modified low density lipoprotein with intimal cells in atherosclerotic lesion].

In the present review we focus on the major cellular and molecular processes leading to the formation and accumulation of foamy cells: increased transmigration of monocytes into sub-endothelial sites of inflammation, activation of macrophages, modifications of lipoproteins, different types of uptake of native and associated lipoproteins (endocytosis, phagocytosis, and less-investigated--patocytosis), as well as participation of different molecular systems in the reverse cholesterol transport in macrophages. Special attention is given to the recent data indicating that scavenger receptors participate not only in the uptake of modified lipoproteins, but also in the reverse cholesterol transport. In conclusion, we discuss most relevant open questions in our understanding of the mechanism and functional consequences of macrophage/lipoprotein interactions: which receptor systems are used for the recognition and internalisation of aggregated lipoproteins, what are the mechanisms of intracellular processing of associated lipoproteins, and how associated lipoproteins affect functional programming of macrophages.