Intratumoral tertiary lymphoid structures (TLSs) have been associated with improved outcome in various cohorts of patients with cancer, reflecting their contribution to the development of tumor-targeting immunity. Here, we demonstrate that high-grade serous ovarian carcinoma (HGSOC) contains distinct immune aggregates with varying degrees of organization and maturation. Specifically, mature TLSs (mTLS) as forming only in 16% of HGSOCs with relatively elevated tumor mutational burden (TMB) are associated with an increased intratumoral density of CD8+ effector T (TEFF) cells and TIM3+PD1+, hence poorly immune checkpoint inhibitor (ICI)-sensitive, CD8+ T cells. Conversely, CD8+ T cells from immunologically hot tumors like non-small cell lung carcinoma (NSCLC) are enriched in ICI-responsive TCF1+ PD1+ T cells. Spatial B-cell profiling identifies patterns of in situ maturation and differentiation associated with mTLSs. Moreover, B-cell depletion promotes signs of a dysfunctional CD8+ T cell compartment among tumor-infiltrating lymphocytes from freshly isolated HGSOC and NSCLC biopsies. Taken together, our data demonstrate that - at odds with NSCLC - HGSOC is associated with a low density of follicular helper T cells and thus develops a limited number of mTLS that might be insufficient to preserve a ICI-sensitive TCF1+PD1+ CD8+ T cell phenotype. These findings point to key quantitative and qualitative differences between mTLSs in ICI-responsive vs ICI-irresponsive neoplasms that may guide the development of alternative immunotherapies for patients with HGSOC.

• MeSH
• CD8-pozitivní T-lymfocyty MeSH
• ektopické lymfoidní struktury * MeSH
• fenotyp MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• nádory plic * MeSH
• nádory vaječníků * patologie   MeSH
• nemalobuněčný karcinom plic * MeSH
• tumor infiltrující lymfocyty MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICI) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication. EXPERIMENTAL DESIGN: We harnessed a variety of transcriptomic, spatial, and functional assays to characterize the differential impact of neoadjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to neoadjuvant chemotherapy (NACT)-naïve HGSOC samples from five independent patient cohorts. RESULTS: We found NACT-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD1+ CD8+ T cells over their ICI-insensitive TIM-3+PD1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden. CONCLUSIONS: Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC. See related commentary by Bravo Melgar and Laoui, p. 10.

• MeSH
• CD8-pozitivní T-lymfocyty * imunologie   účinky léků   MeSH
• ektopické lymfoidní struktury * imunologie   patologie   MeSH
• hepatocytární jaderný faktor 1-alfa * genetika   metabolismus   MeSH
• inhibitory kontrolních bodů * terapeutické užití   farmakologie   MeSH
• karboplatina aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nádorové mikroprostředí * imunologie   účinky léků   MeSH
• nádory vaječníků * farmakoterapie   imunologie   patologie   MeSH
• neoadjuvantní terapie metody   MeSH
• paclitaxel aplikace a dávkování   terapeutické užití   farmakologie   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   farmakologie   MeSH
• serózní cystadenokarcinom farmakoterapie   patologie   imunologie   MeSH
• stres endoplazmatického retikula účinky léků   imunologie   MeSH
• tumor infiltrující lymfocyty imunologie   účinky léků   metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hepatocytární jaderný faktor 1-alfa * MeSH
• inhibitory kontrolních bodů * MeSH
• karboplatina MeSH
• paclitaxel MeSH

BACKGROUND: Prostate cancer (PCa) is a malignancy with significant immunosuppressive properties and limited immune activation. This immunosuppression is linked to reduced cytotoxic T cell activity, impaired antigen presentation, and elevated levels of immunosuppressive cytokines and immune checkpoint molecules. Studies demonstrate that cytotoxic CD8+ T cell infiltration correlates with improved survival, while increased regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) are associated with worse outcomes and therapeutic resistance. Th1 cells are beneficial, whereas Th17 cells, producing interleukin-17 (IL-17), contribute to tumor progression. Tumor-associated neutrophils (TANs) and immune checkpoint molecules, such as PD-1/PD-L1 and T cell immunoglobulin-3 (TIM-3) are also linked to advanced stages of PCa. Chemotherapy holds promise in converting the "cold" tumor microenvironment (TME) to a "hot" one by depleting immunosuppressive cells and enhancing tumor immunogenicity. SUMMARY: This comprehensive review examines the immune microenvironment in PCa, focusing on the intricate interactions between immune and tumor cells in the TME. It highlights how TAMs, Tregs, cytotoxic T cells, and other immune cell types contribute to tumor progression or suppression and how PCa's low immunogenicity complicates immunotherapy. KEY MESSAGES: The infiltration of cytotoxic CD8+ T cells and Th1 cells correlates with better outcomes, while elevated T regs and TAMs promote tumor growth, metastasis, and resistance. TANs and natural killer (NK) cells exhibit dual roles, with higher NK cell levels linked to better prognoses. Immune checkpoint molecules like PD-1, PD-L1, and TIM-3 are associated with advanced disease. Chemotherapy can improve tumor immunogenicity by depleting T regs and myeloid-derived suppressor cells, offering therapeutic promise.

• Klíčová slova
• CD4, CD8, Immunology, Immunotherapy, Metastatic, Myeloid-derived suppressor cells, Neutrophils, Prostate tumor, T cells, Tertiary lymphoid structures, Tumor-associated macrophages,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

CHIP is a tetratricopeptide repeat (TPR) domain protein that functions as an E3-ubiquitin ligase. As well as linking the molecular chaperones to the ubiquitin proteasome system, CHIP also has a docking-dependent mode where it ubiquitinates native substrates, thereby regulating their steady state levels and/or function. Here we explore the effect of Hsp70 on the docking-dependent E3-ligase activity of CHIP. The TPR-domain is revealed as a binding site for allosteric modulators involved in determining CHIP's dynamic conformation and activity. Biochemical, biophysical and modeling evidence demonstrate that Hsp70-binding to the TPR, or Hsp70-mimetic mutations, regulate CHIP-mediated ubiquitination of p53 and IRF-1 through effects on U-box activity and substrate binding. HDX-MS was used to establish that conformational-inhibition-signals extended from the TPR-domain to the U-box. This underscores inter-domain allosteric regulation of CHIP by the core molecular chaperones. Defining the chaperone-associated TPR-domain of CHIP as a manager of inter-domain communication highlights the potential for scaffolding modules to regulate, as well as assemble, complexes that are fundamental to protein homeostatic control.

• MeSH
• alosterická regulace MeSH
• exprese genu MeSH
• interferonový regulační faktor 1 genetika   metabolismus   MeSH
• kinetika MeSH
• lidé MeSH
• lymfocyty cytologie   metabolismus   MeSH
• mapování interakce mezi proteiny MeSH
• molekulární modely MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 genetika   metabolismus   MeSH
• proteasomový endopeptidasový komplex metabolismus   MeSH
• proteiny tepelného šoku HSP70 chemie   genetika   metabolismus   MeSH
• sekundární struktura proteinů MeSH
• terciární struktura proteinů MeSH
• ubikvitinace MeSH
• ubikvitinligasy chemie   genetika   metabolismus   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interferonový regulační faktor 1 MeSH
• nádorový supresorový protein p53 MeSH
• proteasomový endopeptidasový komplex MeSH
• proteiny tepelného šoku HSP70 MeSH
• STUB1 protein, human MeSH Prohlížeč
• ubikvitinligasy MeSH

Lens epithelium-derived growth factor (LEDGF/p75) is an epigenetic reader and attractive therapeutic target involved in HIV integration and the development of mixed lineage leukaemia (MLL1) fusion-driven leukaemia. Besides HIV integrase and the MLL1-menin complex, LEDGF/p75 interacts with various cellular proteins via its integrase binding domain (IBD). Here we present structural characterization of IBD interactions with transcriptional repressor JPO2 and domesticated transposase PogZ, and show that the PogZ interaction is nearly identical to the interaction of LEDGF/p75 with MLL1. The interaction with the IBD is maintained by an intrinsically disordered IBD-binding motif (IBM) common to all known cellular partners of LEDGF/p75. In addition, based on IBM conservation, we identify and validate IWS1 as a novel LEDGF/p75 interaction partner. Our results also reveal how HIV integrase efficiently displaces cellular binding partners from LEDGF/p75. Finally, the similar binding modes of LEDGF/p75 interaction partners represent a new challenge for the development of selective interaction inhibitors.

• MeSH
• dimerizace MeSH
• Escherichia coli MeSH
• histonlysin-N-methyltransferasa metabolismus   MeSH
• HIV-integrasa metabolismus   MeSH
• konsenzuální sekvence MeSH
• Lentivirus enzymologie   MeSH
• lidé MeSH
• mezibuněčné signální peptidy a proteiny metabolismus   MeSH
• molekulární sekvence - údaje MeSH
• proteiny vázající RNA MeSH
• proteiny metabolismus   MeSH
• protoonkogenní protein MLL metabolismus   MeSH
• represorové proteiny metabolismus   MeSH
• sekvence aminokyselin MeSH
• terciární struktura proteinů MeSH
• transkripční faktory MeSH
• transposasy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CDCA7L protein, human MeSH Prohlížeč
• histonlysin-N-methyltransferasa MeSH
• HIV-integrasa MeSH
• Iws1 protein, human MeSH Prohlížeč
• KMT2A protein, human MeSH Prohlížeč
• lens epithelium-derived growth factor MeSH Prohlížeč
• mezibuněčné signální peptidy a proteiny MeSH
• POGZ protein, human MeSH Prohlížeč
• proteiny vázající RNA MeSH
• proteiny MeSH
• protoonkogenní protein MLL MeSH
• represorové proteiny MeSH
• transkripční faktory MeSH
• transposasy 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

Oestrus synchronization was studied in samples from six cows of the Black-Pied Lowland breed. Three cows four to five days from oestrus were used as the control; three animals with marked periodic corpora lutea were given an i. m. injection of 0.5 mg cloprostenol. The eighth day from the administration of the preparation, the ovaries of the cows were excised and, after histological processing in a simultaneous series in a 4mm interval, the preparations were subjected to qualitative and quantitative microscopic evaluation. The structure of non-atretic and atretic follicles was described in different stages of the atretic process. The lymphoid cells of atretic follicles were observed to penetrate into the granulosa membrane. A multiplication of non-atretic tertiary follicles was observed after the administration of cloprostenol. This multiplication was more pronounced on the right ovary where the preceding ovulation had taken place (P less than 0.01). The treated animals, compared with the controls, showed a significant multiplication of tertiary follicles at early atresia and at total collapse atresia (P less than 0.001), whereas the number of follicles with contractive atresia showed a significant decrease (P less than 0.001). The results suggest that cloprostenol can influence follicle population mostly through the stimulation of the growth and ripening of tertiary follicles; its modulation effect seems manifest itself in cooperating relation with gonadotrophic hormones, mainly with the follicular secondary hormone (FSH), in the theory of the complex effect of proteohormones .

• MeSH
• cloprostenol farmakologie   MeSH
• luteolytické látky farmakologie   MeSH
• ovariální folikul cytologie   účinky léků   MeSH
• prostaglandiny F syntetické farmakologie   MeSH
• skot fyziologie   MeSH
• synchronizace říje * MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• skot fyziologie   MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• cloprostenol MeSH
• luteolytické látky MeSH
• prostaglandiny F syntetické MeSH

Liposarcomas (LPS) are the most frequent malignancies in the soft tissue sarcoma family and consist of five distinctive histological subtypes, termed well-differentiated LPS, dedifferentiated LPS (DDLPS), myxoid LPS (MLPS), pleomorphic LPS, and myxoid pleomorphic LPS. They display variations in genetic alterations, clinical behavior, and prognostic course. While accumulating evidence implicates a crucial role of the tumor immune contexture in shaping the response to anticancer treatments, the immunological landscape of LPS is highly variable across different subtypes. Thus, DDLPS is characterized by a higher abundance of infiltrating T cells, yet the opposite was reported for MLPS. Interestingly, a recent study indicated that the frequency of pre-existing T cells in soft tissue sarcomas has a predictive value for immune checkpoint inhibitor (CPI) therapy. Additionally, B cells and tertiary lymphoid structures were identified as potential biomarkers for the clinical outcome of LPS patients and response to CPI therapy. Furthermore, it was demonstrated that macrophages, predominantly of M2 polarization, are frequently associated with poor prognosis. An improved understanding of the complex LPS immune contexture enables the design and refinement of novel immunotherapeutic approaches. Here, we summarize recent studies focusing on the clinicopathological, genetic, and immunological determinants of LPS.

• Klíčová slova
• immune architecture, immunotherapy, liposarcoma,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, APO2L) has been shown to induce apoptosis in a number of tumor cell lines as well as in some primary tumors whereas cells from most normal tissues are highly resistant to TRAIL-induced apoptosis. We have studied the susceptibility of primary malignant and normal bone marrow hematopoietic progenitors to TRAIL-induced apoptosis. Extracellular domain of human TRAIL with N-terminal His(6) tag (His-TRAIL, amino acids 95-281) was produced in E. coli and its apoptosis-inducing ability was compared with the leucine-zipper containing TRAIL, LZ-TRAIL. Both variants of TRAIL had the same apoptosis-inducing ability. Clonogenic progenitor assays showed that His-TRAIL significantly reduced the number of myeloid colonies (CFU-GM) and clusters from patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndromes (MDS). His-TRAIL had no negative effect on the number of CFU-GM colonies and clusters derived from bone marrow cells of AML patients in complete remission, and lymphoma patients without bone marrow involvement, as well as those derived from normal cord blood cells. Moreover, we found that normal human stem cells treated with high doses of His-TRAIL maintain a repopulating potential when transplanted into NOD/SCID mice. To conclude, our data document that TRAIL does not affect normal human hematopoiesis but suppresses the growth of early primary leukemia and myelodysplasia progenitors.

• MeSH
• akutní nemoc MeSH
• analýza kolonii tvořících jednotek MeSH
• apoptóza účinky léků   MeSH
• buněčná diferenciace účinky léků   MeSH
• buňky K562 účinky léků   MeSH
• hematopoetické kmenové buňky účinky léků   MeSH
• HL-60 buňky účinky léků   MeSH
• inhibitory růstu farmakologie   MeSH
• Jurkat buňky účinky léků   MeSH
• kultivované buňky účinky léků   MeSH
• leucinové zipy MeSH
• lidé MeSH
• membránové glykoproteiny chemie   genetika   farmakologie   MeSH
• myelodysplastické syndromy patologie   MeSH
• myeloidní buňky účinky léků   MeSH
• myeloidní leukemie patologie   MeSH
• myši inbrední BALB C MeSH
• myši inbrední NOD MeSH
• myši SCID MeSH
• myši MeSH
• nádorové buňky kultivované účinky léků   MeSH
• nádorové kmenové buňky účinky léků   MeSH
• nehodgkinský lymfom patologie   MeSH
• peptidové fragmenty chemie   genetika   farmakologie   MeSH
• přežívání štěpu MeSH
• protinádorové látky farmakologie   MeSH
• rekombinantní fúzní proteiny chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• terciární struktura proteinů MeSH
• testy nádorových kmenových buněk MeSH
• TNF-alfa chemie   genetika   farmakologie   MeSH
• transplantace hematopoetických kmenových buněk MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• His-TRAIL protein, recombinant MeSH Prohlížeč
• inhibitory růstu MeSH
• LZ-TRAIL protein, recombinant MeSH Prohlížeč
• membránové glykoproteiny MeSH
• peptidové fragmenty MeSH
• protinádorové látky MeSH
• rekombinantní fúzní proteiny MeSH
• TNF-alfa MeSH