PURPOSE: In multiple oncological settings, expression of the coinhibitory ligand PD-L1 by malignant cells and tumor infiltration by immune cells expressing coinhibitory receptors such as PD-1, CTLA4, LAG-3, or TIM-3 conveys prognostic or predictive information. Conversely, the impact of these features of the tumor microenvironment on disease outcome among high-grade serous carcinoma (HGSC) patients remains controversial. EXPERIMENTAL DESIGN: We harnessed a retrospective cohort of 80 chemotherapy-naïve HGSC patients to investigate PD-L1 expression and tumor infiltration by CD8+ T cells, CD20+ B cells, DC-LAMP+ dendritic cells as well as by PD-1+, CTLA4+, LAG-3+, and TIM-3+ cells in relation with prognosis and function orientation of the tumor microenvironment. IHC data were complemented with transcriptomic and functional studies on a second prospective cohort of freshly resected HGSC samples. In silico analysis of publicly available RNA expression data from 308 HGSC samples was used as a confirmatory approach. RESULTS: High levels of PD-L1 and high densities of PD-1+ cells in the microenvironment of HGSCs were strongly associated with an immune contexture characterized by a robust TH1 polarization and cytotoxic orientation that enabled superior clinical benefits. Moreover, PD-1+TIM-3+CD8+ T cells presented all features of functional exhaustion and correlated with poor disease outcome. However, although PD-L1 levels and tumor infiltration by TIM-3+ cells improved patient stratification based on the intratumoral abundance of CD8+ T cells, the amount of PD-1+ cells failed to do so. CONCLUSIONS: Our data indicate that PD-L1 and TIM-3 constitute prognostically relevant biomarkers of active and suppressed immune responses against HGSC, respectively.

• MeSH
• antigen CTLA-4 imunologie   metabolismus   MeSH
• antigeny CD274 imunologie   metabolismus   MeSH
• buněčný receptor 2 viru hepatitidy A imunologie   metabolismus   MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• dospělí MeSH
• epiteliální ovariální karcinom imunologie   metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové glykoproteiny asociované s lyzozomy imunologie   metabolismus   MeSH
• míra přežití MeSH
• nádorové biomarkery imunologie   metabolismus   MeSH
• nádorové proteiny imunologie   metabolismus   MeSH
• prognóza MeSH
• regulace genové exprese u nádorů * MeSH
• retrospektivní studie MeSH
• senioři MeSH
• serózní cystadenokarcinom imunologie   metabolismus   patologie   MeSH
• tumor infiltrující lymfocyty imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• antigen CTLA-4 MeSH
• antigeny CD274 MeSH
• buněčný receptor 2 viru hepatitidy A MeSH
• CD274 protein, human MeSH Prohlížeč
• CTLA4 protein, human MeSH Prohlížeč
• HAVCR2 protein, human MeSH Prohlížeč
• LAMP3 protein, human MeSH Prohlížeč
• membránové glykoproteiny asociované s lyzozomy MeSH
• nádorové biomarkery MeSH
• nádorové proteiny MeSH

A high density of tumor-infiltrating CD8+ T cells and CD20+ B cells correlates with prolonged survival in patients with a wide variety of human cancers, including high-grade serous ovarian carcinoma (HGSC). However, the potential impact of mature dendritic cells (DCs) in shaping the immune contexture of HGSC, their role in the establishment of T cell-dependent antitumor immunity, and their potential prognostic value for HGSC patients remain unclear. We harnessed immunohistochemical tests and biomolecular analyses to demonstrate that a high density of tumor-infiltrating DC-LAMP+ DCs is robustly associated with an immune contexture characterized by TH1 polarization and cytotoxic activity. We showed that both mature DCs and CD20+ B cells play a critical role in the generation of a clinically-favorable cytotoxic immune response in HGSC microenvironment. In line with this notion, robust tumor infiltration by both DC-LAMP+ DCs and CD20+ B cells was associated with most favorable overall survival in two independent cohorts of chemotherapy-naïve HGSC patients. Our findings suggest that the presence of mature, DC-LAMP+ DCs in the tumor microenvironment may represent a novel, powerful prognostic biomarker for HGSC patients that reflects the activation of clinically-relevant anticancer immunity.

• Klíčová slova
• CD8+ cytotoxic T lymphocytes, DC-LAMP, Dendritic cells, Natural killer cells, Tertiary lymphoid structures,
• MeSH
• biologické markery MeSH
• dendritické buňky imunologie   metabolismus   patologie   MeSH
• dospělí MeSH
• imunofenotypizace MeSH
• imunohistochemie MeSH
• Kaplanův-Meierův odhad MeSH
• karcinom imunologie   mortalita   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové mikroprostředí imunologie   MeSH
• nádory vaječníků imunologie   mortalita   patologie   terapie   MeSH
• prognóza MeSH
• proporcionální rizikové modely MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• T-lymfocyty - podskupiny imunologie   metabolismus   patologie   MeSH
• tumor infiltrující lymfocyty imunologie   metabolismus   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH

Calcific aortic valve disease is considered a form of atherosclerosis and, like the latter, possibly of inflammatory origin. The aim of our work was to study the pattern of cellular infiltrate in calcific aortic valve stenosis (CAS). Fifteen operatively excised calcified aortic valves were examined by histology and immunohistochemistry (CD20, CD79α, CD3, CD4, CD8, CD68, CD138, CD117, BJK, BJL, IgA, IgD, IgG, IgG4 and IgM). The findings revealed that in CAS, there were chronic inflammatory features with infiltrates comprising lymphocytes, polyclonal plasma cells, histiocytes and mast cells. In T-lymphocytes, CD4 prevailed over CD8. In B-lymphocytes, there was a slight preponderance of CD20 over CD79α. The BJL (lambda)-positive plasma cells prevailed over the BJK (kappa) ones. The CD138-positive plasma cells comprised 24% IgA-, 20% IgD-, 41% IgG- (including 11% of IgG4-) and 15% IgM-positive cells. CAS did not fulfill the criteria of the recently described clinicopathological entity IgG4-related sclerosing systemic disease. The inflammatory process was the same in both subsets of CAS - those with trileaflet (normally formed) valves and those with congenitally bicuspid valves.

• MeSH
• aortální chlopeň metabolismus   patologie   chirurgie   MeSH
• aortální stenóza metabolismus   patologie   chirurgie   MeSH
• B-lymfocyty metabolismus   patologie   MeSH
• biologické markery metabolismus   MeSH
• CD antigeny metabolismus   MeSH
• histiocyty metabolismus   patologie   MeSH
• imunitní systém metabolismus   patologie   MeSH
• imunoglobuliny metabolismus   MeSH
• kalcinóza metabolismus   patologie   chirurgie   MeSH
• lidé MeSH
• mastocyty metabolismus   patologie   MeSH
• patologická angiogeneze patologie   MeSH
• plazmatické buňky metabolismus   patologie   MeSH
• senioři MeSH
• T-lymfocyty metabolismus   patologie   MeSH
• zánět metabolismus   patologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• CD antigeny MeSH
• imunoglobuliny MeSH

BACKGROUND/AIM: Tumour-infiltrating lymphocytes (TILs) and Granzyme B play crucial roles in immune reactions against colorectal carcinoma (CRCa). The inhibitor of Granzyme B is Serpin B9. The aim of this study was to evaluate the effect of immunohistological parameters of TILs on the prognosis of CRCa and presence of lymph node metastasis. PATIENTS AND METHODS: A total of 152 patients who underwent surgery for CRCa were analyzed, including 63 patients in cohort stage II, according to the Union for International Cancer Control (UICC), and 89 patients in cohort UICC stage III. The TIL pattern was classified as peritumoural (PTL), intratumoural (ITL), intrastromal (ISL) or Crohn-like, and immunohistological staining of TIL and cancer cells was also performed. RESULTS: A significantly higher density of CD8+ and CD4+ TILs was observed in the UICC II group, and significantly higher densities of CD4+ TILs were observed in the UICC II group in all distinguished patterns. In the same cohort, higher numbers of CD57+ cells and FoxP3+ TILs and Granzyme B levels were observed. In cohort UICC III, there was a higher density of ISL, PTL CD8+, CD25+ TILs and cancer cells showed staining for Serpin B9. CD57, Granzyme B and CD8 were demonstrated as positive prognostic factors of overall survival, and CD57 and CD4+ TILs were demonstrated as positive prognostic factors of recurrence. CONCLUSION: TILs and CD57 are promising prognostic factors of CRCa. The association of Serpin B9 with lymph node metastasis reveals a potential mechanism for tumour resistance to immune reaction.

• Klíčová slova
• CD25, CD4, CD56, CD57, CD8, Colorectal carcinoma, FoxP3, Serpin B9, lymph node metastasis, natural killer cells, recurrence, tumour-infiltrating lymphocytes,
• MeSH
• kolorektální nádory imunologie   patologie   MeSH
• lidé MeSH
• lymfatické metastázy imunologie   patologie   MeSH
• nádorové biomarkery imunologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• tumor infiltrující lymfocyty imunologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• nádorové biomarkery MeSH

BACKGROUND: The tumor microenvironment is a significant mediator enabling tumor growth and progression. Tumor-infiltrating lymphocytes (TILs) are an important component of this but tumor cells develop mechanisms by which they can escape the action of the immune system. Immunosuppressive mechanisms cooperate with each other and involve cells of the immune system, the tumor microenvironment itself, chemokines and cytokines. In this study, we examined the FOXP3+, IL-35+, and PD-L1+ lymphocytes in tumor tissues as they are contributing to immunosuppression in some tumors, including melanoma. Such cells are also associated with tumor progression, early metastasis, and prognosis. METHODS AND RESULTS: In this study, 95 cutaneous melanomas and 25 melanocytic nevi as a control group were examined by immunohistochemistry for FOXP3+, IL-35+, and PD-L1+ lymphocytes. Melanomas were divided into four groups according to the TNM classification: pT1 (35), pT2 (21), pT3 (21), and pT4 (18). PD-L1+ lymphocytes were enriched in pT3- and pT4-stage melanomas, especially in the periphery of the lesions (P<0.001). The number of FOXP3+ lymphocytes was positively correlated with the stage of the disease, especially in the center of the tumors (P<0.001). Likewise, IL-35+ lymphocytes (P<0.001) were enriched with the stage of the tumor. CONCLUSION: This article demonstrates that the immunosuppressive environment develops in proportion to the stage of the melanoma. The most significant changes are found at the tumor periphery, confirming the heterogeneity of the tumor stroma which is more pronounced in more advanced tumors and which may contribute to the greater aggressiveness in these peripheral zones.

• Klíčová slova
• cutaneous melanoma, immune checkpoints, immunosuppression, tumor microenvironment, tumor-infiltrating lymphocytes,
• Publikační typ
• časopisecké články MeSH

Colorectal cancer (CRC) is one of the leading cancers in both genders. TNM staging system is still the most commonly used tumor classification and prognostic system. The disadvantage of TNM is that the prognostic information it provides is incomplete, and patients with the same histological tumor stages may differ significantly in the clinical outcome. Therefore, the identification of new prognostic parameters is crucial. The carcinogenic process that gives rise to an individual tumor is unique and tumor microenviroment should be taken into consideration. In CRC, T-cell infiltration is not homogenous, and recent studies are mostly focusing on memory T-cells and CD8 cells in predicting disease-free survival (DFS) and overall survival (OS). It seems that DFS and OS are not only dependent on microsatellite instable or stable status but mostly on the levels of expression of the immune signatures. Also, patients with high infiltration of cytotoxic and memory cells have significantly better outcome. This review consolidates current knowledge and recent research about importance of immune-cell-associated proteins, specific gene profiles of immune cells and immunotherapy in CRC. We also discussed cell-specific signatures in cancer treatment.

• Klíčová slova
• Colorectal cancer (CRC), Genomic profile, Immune cells, Immunotherapy,
• MeSH
• imunoterapie MeSH
• inhibitory kontrolních bodů terapeutické užití   MeSH
• kolorektální nádory genetika   imunologie   patologie   MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• prognóza MeSH
• sekvenční analýza RNA MeSH
• staging nádorů MeSH
• výpočetní biologie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• inhibitory kontrolních bodů MeSH

Penile squamous cell carcinoma (pSCC) is a rare malignancy with a slowly increasing incidence and variable prognosis. Regional lymph node involvement signifies poor prognosis but represents a late sign, and more prognostic markers for effective patient risk stratification are urgently needed. In this retrospective study, 152 tumour samples with formalin-fixed, paraffin-embedded tissue were analysed for traditional pathological variables, tumour budding, p53, p16, and mismatch repair proteins (MMR) immunohistochemistry. The density of tumour lymphocytic infiltrate was also determined, using subjective evaluation by two pathologists (brisk/non-brisk/absent) and also using the immunoscore method, which categorised the cohort into five immunoscore groups according to the number of CD3+ and CD8+ T-cells in both the tumour centre and tumour invasion front. Only one case (0.6%) was MMR-deficient. Tumour budding count ≥5 tumour buds/20× power field and non-brisk/absent lymphocytic infiltrate were significant negative predictors of both the overall survival (OS) and cancer-specific survival (CSS), whereas a low immunoscore was a significant marker of shorter OS but not CSS. Advanced pT stage (3+4) was a significant marker of shorter CSS but not OS. In the multivariate analysis, high-grade budding was a significant parameter if adjusted for the patient's age and associated variables, except for the pN stage. The lymphocytic infiltrate retained its prognostic significance if adjusted for age and associated variables. The negative prognostic significance of the previously described parameters (lymphatic, venous, and perineural invasion, regional lymph node metastasis, and p53 mutated profile) were confirmed in our study. Grade, histological subtype, and HPV status (as determined by p16 immunohistochemistry) showed, surprisingly, little or no prognostic significance.

• Klíčová slova
• CD3, CD8, Penile, brisk, budding, cancer, immunoscore, lymphocytic infiltrate, non-brisk, p16 HPV, p53, penis, squamous cell carcinoma, tumour infiltrating lymphocytes,
• MeSH
• lidé MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• nádory penisu * patologie   MeSH
• prognóza MeSH
• retrospektivní studie MeSH
• spinocelulární karcinom * patologie   MeSH
• zánět MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• nádorový supresorový protein p53 MeSH

Tumour microenvironment contributes to growth and metastasis, where angiogenesis and immune alteration suppressing its effectory function belong to main factors. Our study is focused on an analysis of microvascular density (MVD), quantification of FOXP3+ T regulatory lymphocytes (Tregs) and PD-L1 lymphocytes, which are associated with a tumour-cells immune escape mechanism. We examined 95 cutaneous melanomas devided in four groups according to TNM classification - pT1 (35), pT2 (21), pT3 (21), pT4 (18) and 25 melanocytic nevi as a control group. Investigated parameters were detected on paraffin embedded tissues by indirect immunohistochemistry, and evaluated by light microscope in central (C) and at peripheral regions (P) on a 1mm2 „hot spot“ region (the area of the highest density). We found a significant MVD increase correlating with a stage of disease, mostly at the edge of tumours (p=0,0001). Lymphocytic PD-L1 expresion was increased in melanomas of pT3 and pT4 stages, also predominantly at the periphery of lesions (p=0,0001). Numbers of FOXP3 lymphocytes positively correlated with a melanoma stage, where higher values were observed in central areas (p=0,008). Our study documents that stimulation of angiogenesis and induction of an adaptive immune response correlate with a melanoma stage. The most prominent changes are at the tumour periphery confirming heterogeneity of a tumour stroma, which is more prominent in advanced tumours, and which may contribute to higher agresivity of these stages.

• Klíčová slova
• Angiogenesis, CD90, FOXP3, Nestin, PD-L1, TIL, Tregs,
• MeSH
• lidé MeSH
• melanom * MeSH
• nádorové mikroprostředí MeSH
• nádory kůže * MeSH
• patologická angiogeneze MeSH
• staging nádorů MeSH
• tumor infiltrující lymfocyty MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The insight into the biological nature of head and neck squamous cell carcinoma has evolved significantly in the last few years. Tobacco use and alcohol consumption are proven risk factors of head and neck squamous cell carcinoma. Cancer patients possessing such a tumor are generally elderly, mostly in fifth or sixth decade of life. In addition, significant association of head and neck squamous cell carcinoma with infection by human papillomavirus (HPV) was proven. HPV is now considered to be one of the most important risk factors, particularly for oropharyngeal carcinoma. HPV positive tumors of oropharynx are associated with significantly better prognosis. Experimental and clinical data indicate that HPV positive and HPV negative tumors can be considered as two different entities and it has not been clarified which factors are crucial for better prognosis of HPV positive tumors. The character of immune reaction, which contributes to distinct prognosis, may be one of the important factors. This review summarizes current knowledge concerning various aspects of antitumor immune responses in HPV positive and HPV negative tumors. Recent studies have shown that a broad repertoire of tumor infiltrating HPV specific T-cells is detectable in almost all patients with HPV positive tumors. Despite this, there is a development of tumor, which may be facilitated by abnormalities in antigen processing, T-cell dysfunction or prevalence of immunosuppressive cells. Nonetheless, the immunologic profile of HPV positive vs. HPV negative head and neck squamous cell carcinoma is associated with better outcome, and HPV specific immune response is suggested to play an essential role in the better response to conventional therapy of HPV positive patients. We also discuss HPV specific antitumor immunotherapy approaches, which are now tested in clinical trials.

• MeSH
• imunitní systém imunologie   MeSH
• imunoterapie MeSH
• infekce papilomavirem komplikace   MeSH
• lidé MeSH
• nádory hlavy a krku etiologie   imunologie   terapie   MeSH
• T-lymfocyty imunologie   MeSH
• tumor infiltrující lymfocyty imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Lysosomes are crucial in the tumour immune microenvironment, which is essential for the survival and homeostasis in multiple myeloma (MM). Here, we aimed to identify lysosome-related genes for the prognosis of MM and predicted their regulatory mechanisms. Gene expression profiles of MM from the GSE2658 and GSE57317 datasets were analysed. Lysosome-related differentially expressed genes (DEGs) were identified and used for molecular subtyping of MM patients. A prognostic model was constructed using univariate Cox regression and LASSO regression analyses. The relationship between prognostic genes, immune cell types, and autophagy pathways was assessed through correlation analysis. RT-qPCR was performed to validate the expression of prognostic genes in MM cells. A total of 9,954 DEGs were identified between high and low immune score groups, with 213 intersecting with lysosomal genes. Molecular subtyping revealed two distinct MM subtypes with significant differences in immune cell types and autophagy pathway activities. Five lysosome-related DEGs (CORO1A, ELANE, PSAP, RNASE2, and SNAPIN) were identified as significant prognostic markers. The prognostic model showed moderate predictive accuracy with AUC values up to 0.723. Prognostic genes demonstrated significant correlations with various immune cell types and autophagy pathways. Additionally, CORO1A, PSAP and RNASE2 expression was up-regulated in MM cells, while ELANE and SNAPIN were down-regulated. Five lysosomal genes in MM were identified, and a new risk model for prognosis was developed using these genes. This research could lead to discovering important gene markers for the treatment and prognosis of MM.

• Klíčová slova
• autophagy, immune score, lysosome, multiple myeloma, prognostic model,
• MeSH
• autofagie genetika   MeSH
• lidé MeSH
• lyzozomy * metabolismus   genetika   MeSH
• mnohočetný myelom * genetika   imunologie   MeSH
• nádorové biomarkery genetika   MeSH
• nádorové mikroprostředí genetika   imunologie   MeSH
• prognóza MeSH
• regulace genové exprese u nádorů MeSH
• stanovení celkové genové exprese MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• nádorové biomarkery MeSH