Tumorigenicity of two thymic lymphoma cell lines BW5147 (H-2k/H-2k; HGPRT-) and EL-4R (H-2b/H-2b; TK-) was compared with that of their hybrid cell line BH2 (H-2k/H-2k x H-2b/H-2b; HGPRT+; TK+). Tumour inocula from the parental and hybrid cell lines grew in syngeneic but not allogeneic recipients; the possible admixture of the revertant parental cells (BW5147HGPRT+, EL-4RTK+) in the hybrid cell population was, according to the transplantation tests, lower than 10(-4). The tumorigenicity of the hybrid cell line BH2 in the (B10 X AKR)F1 hybrid recipients was substantially lower than the tumorigenicity of the parental cell lines in both semisyngeneic (B10 X AKR)F1 and syngeneic mice.

• MeSH
• buněčné linie MeSH
• experimentální nádory patofyziologie   MeSH
• fúze buněk MeSH
• hybridní buňky MeSH
• inbrední kmeny myší MeSH
• lymfom patofyziologie   MeSH
• mutace MeSH
• myši MeSH
• nádory brzlíku patofyziologie   MeSH
• T-lymfocyty fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

T-cell lymphomas (TCLs) are a rare and heterogeneous subgroup of non-Hodgkin lymphomas (NHLs), forming only 10 % of all NHL cases in Western countries. Resulting from their low incidence and heterogeneity, the current treatment outcome is generally unfavorable, with limited availability of novel therapeutic approaches. Therefore, the recent success of immune checkpoint inhibitors (ICIs) in cancer treatment motivated their clinical investigation in TCLs as well. Multiple studies showed promising results; however, cases of TCL hyperprogression following ICI treatment and secondary T-cell-derived malignancies associated with ICI treatment of other cancer types were also reported. In our review, we first briefly summarize classification of T-cell-derived malignancies, general anti-tumor immune response, immune evasion, and immune checkpoint signaling. Next, we provide an overview of immune checkpoint molecule deregulation in TCLs, summarize available studies of ICIs in TCLs, and review the above-mentioned safety concerns associa-ted with ICI treatment and T-cell-derived malignancies. Despite initial promising results, further studies are necessary to define the most suitable clinical applications and ICI therapeutic combinations with other novel treatment approaches within TCL treatment. ICIs, and their combinations, might hopefully bring the long awaited improvement for the treatment of T-cell-derived malignancies.

• Klíčová slova
• ALCL, CTLA-4, ENKTL, LAG-3, MF, OX40/OX40L, PD-1, PD-L1, PTCL, SS, Sézary syndrome, T-cell lymphoma, T-cell-derived malignancies, TIGIT, TIM-3, anaplastic large cell lymphoma, anti-CTLA-4, anti-PD-1, anti-PD-L1, atezolizumab, avelumab, durvalumab, extranodal NK/T-cell lymphoma, geptanolimab, immune checkpoint inhibitors, immune checkpoints, ipilimumab, mycosis fungoides, nivolumab, pembrolizumab, peripheral T-cell lymphoma, sintilimab, toripalimab,
• MeSH
• inhibitory kontrolních bodů * terapeutické užití   MeSH
• lidé MeSH
• lymfom T-buněčný * farmakoterapie   imunologie   MeSH
• proteiny kontrolních bodů imunitní reakce metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• inhibitory kontrolních bodů * MeSH
• proteiny kontrolních bodů imunitní reakce MeSH

T cell receptor (TCR) recognition of foreign peptides presented by major histocompatibility complex protein is a major event in triggering the adaptive immune response to pathogens or cancer. The prediction of TCR-peptide interactions has great importance for therapy of cancer as well as infectious and autoimmune diseases but remains a major challenge, particularly for novel (unseen) peptide epitopes. Here we present TCRen, a structure-based method for ranking candidate unseen epitopes for a given TCR. The first stage of the TCRen pipeline is modeling of the TCR-peptide-major histocompatibility complex structure. Then a TCR-peptide residue contact map is extracted from this structure and used to rank all candidate epitopes on the basis of an interaction score with the target TCR. Scoring is performed using an energy potential derived from the statistics of TCR-peptide contact preferences in existing crystal structures. We show that TCRen has high performance in discriminating cognate versus unrelated peptides and can facilitate the identification of cancer neoepitopes recognized by tumor-infiltrating lymphocytes.

• MeSH
• epitopy T-lymfocytární imunologie   chemie   MeSH
• epitopy imunologie   chemie   MeSH
• hlavní histokompatibilní komplex imunologie   MeSH
• konformace proteinů MeSH
• lidé MeSH
• molekulární modely MeSH
• nádory imunologie   MeSH
• peptidy imunologie   chemie   MeSH
• receptory antigenů T-buněk * imunologie   chemie   metabolismus   MeSH
• tumor infiltrující lymfocyty imunologie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• epitopy T-lymfocytární MeSH
• epitopy MeSH
• peptidy MeSH
• receptory antigenů T-buněk * MeSH

Thalidomide and its derivatives (lenalidomide, pomalidomide, avadomide, iberdomide hydrochoride, CC-885 and CC-90009) form the family of immunomodulatory drugs (IMiDs). Lenalidomide (CC5013, Revlimid®) was approved by the US FDA and the EMA for the treatment of multiple myeloma (MM) patients, low or intermediate-1 risk transfusion-dependent myelodysplastic syndrome (MDS) with chromosome 5q deletion [del(5q)] and relapsed and/or refractory mantle cell lymphoma following bortezomib. Lenalidomide has also been studied in clinical trials and has shown promising activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Lenalidomide has anti-inflammatory effects and inhibits angiogenesis. Pomalidomide (CC4047, Imnovid® [EU], Pomalyst® [USA]) was approved for advanced MM insensitive to bortezomib and lenalidomide. Other IMiDs are in phases 1 and 2 of clinical trials. Cereblon (CRBN) seems to have an important role in IMiDs action in both lymphoid and myeloid hematological malignancies. Cereblon acts as the substrate receptor of a cullin-4 really interesting new gene (RING) E3 ubiquitin ligase CRL4CRBN. This E3 ubiquitin ligase in the absence of lenalidomide ubiquitinates CRBN itself and the other components of CRL4CRBN complex. Presence of lenalidomide changes specificity of CRL4CRBN which ubiquitinates two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos), and casein kinase 1α (CK1α) and marks them for degradation in proteasomes. Both these transcription factors (IKZF1 and IKZF3) stimulate proliferation of MM cells and inhibit T cells. Low CRBN level was connected with insensitivity of MM cells to lenalidomide. Lenalidomide decreases expression of protein argonaute-2, which binds to cereblon. Argonaute-2 seems to be an important drug target against IMiDs resistance in MM cells. Lenalidomide decreases also basigin and monocarboxylate transporter 1 in MM cells. MM cells with low expression of Ikaros, Aiolos and basigin are more sensitive to lenalidomide treatment. The CK1α gene (CSNK1A1) is located on 5q32 in commonly deleted region (CDR) in del(5q) MDS. Inhibition of CK1α sensitizes del(5q) MDS cells to lenalidomide. CK1α mediates also survival of malignant plasma cells in MM. Though, inhibition of CK1α is a potential novel therapy not only in del(5q) MDS but also in MM. High level of full length CRBN mRNA in mononuclear cells of bone marrow and of peripheral blood seems to be necessary for successful therapy of del(5q) MDS with lenalidomide. While transfusion independence (TI) after lenalidomide treatment is more than 60% in MDS patients with del(5q), only 25% TI and substantially shorter duration of response with occurrence of neutropenia and thrombocytopenia were achieved in lower risk MDS patients with normal karyotype treated with lenalidomide. Shortage of the biomarkers for lenalidomide response in these MDS patients is the main problem up to now.

• Klíčová slova
• Cereblon, Ikaros family, casein kinase 1α1, cullin 4-containing RING E3 ubiquitin ligase complex, del(5q) MDS, immunomodulatory drugs, lenalidomide, mantle lymphoma, multiple myeloma, pomalidomide, proteasome.,
• MeSH
• imunomodulace účinky léků   MeSH
• lidé MeSH
• lymfom farmakoterapie   patologie   MeSH
• myelodysplastické syndromy farmakoterapie   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Malignant melanoma (MM) urgently needs identification of new markers with better predictive value than currently-used clinical and histological parameters. Cancer cells stimulate the formation of a specialized tumor microenvironment, which reciprocally affects uncontrolled proliferation and migration. However, this microenvironment is heterogeneous with different sub-compartments defined by their access to oxygen and nutrients. This study evaluated microvascular density (MVD), CD3+ lymphocytes (TILs) and FOXP3+ T-regulatory lymphocytes (Tregs) on formalin-fixed paraffin-embedded tissue sections using light microscopy. We analyzed 82 malignant melanomas, divided according to the AJCC TNM classification into four groups--pT1 (35), pT2 (17), pT3 (18) and pT4 (12)--and 25 benign pigmented nevi. All parameters were measured in both the central areas of tumors (C) and at their periphery (P). A marked increase in all parameters was found in melanomas compared to nevi (p = 0.0001). There was a positive correlation between MVD, TILs, FOXP3+ Tregs and the vertical growth phase. The results show that MVD, TILs and FOXP3+ Tregs substantially influence cutaneous melanoma microenvironment. We found significant topographic differences of the parameters between central areas of tumors and their boundaries.

• MeSH
• antigeny Thy-1 metabolismus   MeSH
• dospělí MeSH
• forkhead transkripční faktory metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• maligní melanom kůže MeSH
• melanom krevní zásobení   imunologie   patologie   MeSH
• mikrocévy metabolismus   patofyziologie   MeSH
• nádory kůže krevní zásobení   imunologie   patologie   MeSH
• patologická angiogeneze imunologie   patologie   MeSH
• regulační T-lymfocyty imunologie   metabolismus   MeSH
• senioři MeSH
• tumor infiltrující lymfocyty imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny Thy-1 MeSH
• forkhead transkripční faktory MeSH
• FOXP3 protein, human MeSH Prohlížeč

Venetoclax (VEN), a B-cell lymphoma 2 (BCL2) inhibitor, has a promising single-agent activity in mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), and large BCLs, but remissions were generally short, which call for rational drug combinations. Using a panel of 21 lymphoma and leukemia cell lines and 28 primary samples, we demonstrated strong synergy between VEN and A1155463, a BCL-XL inhibitor. Immunoprecipitation experiments and studies on clones with knockout of expression or transgenic expression of BCL-XL confirmed its key role in mediating inherent and acquired VEN resistance. Of note, the VEN and A1155463 combination was synthetically lethal even in the cell lines with lack of expression of the proapoptotic BCL2L11/BIM and in the derived clones with genetic knockout of BCL2L11/BIM. This is clinically important because BCL2L11/BIM deletion, downregulation, or sequestration results in VEN resistance. Immunoprecipitation experiments further suggested that the proapoptotic effector BAX belongs to principal mediators of the VEN and A1155463 mode of action in the BIM-deficient cells. Lastly, the efficacy of the new proapoptotic combination was confirmed in vivo on a panel of 9 patient-derived lymphoma xenografts models including MCL (n = 3), B-ALL (n = 2), T-ALL (n = 1), and diffuse large BCL (n = 3). Because continuous inhibition of BCL-XL causes thrombocytopenia, we proposed and tested an interrupted 4 days on/3 days off treatment regimen, which retained the desired antitumor synergy with manageable platelet toxicity. The proposed VEN and A1155463 combination represents an innovative chemotherapy-free regimen with significant preclinical activity across diverse BCL2+ hematologic malignancies irrespective of the BCL2L11/BIM status.

• MeSH
• antitumorózní látky farmakologie   terapeutické užití   MeSH
• apoptóza účinky léků   MeSH
• benzothiazoly MeSH
• bicyklické sloučeniny heterocyklické * farmakologie   terapeutické užití   MeSH
• chemorezistence * MeSH
• isochinoliny MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• protein bcl-X * metabolismus   antagonisté a inhibitory   MeSH
• protein BCL2L11 * metabolismus   genetika   MeSH
• protoonkogenní proteiny c-bcl-2 metabolismus   antagonisté a inhibitory   MeSH
• sulfonamidy * farmakologie   terapeutické užití   MeSH
• synergismus léků MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• A-1155463 MeSH Prohlížeč
• antitumorózní látky MeSH
• BCL2L1 protein, human MeSH Prohlížeč
• benzothiazoly MeSH
• bicyklické sloučeniny heterocyklické * MeSH
• isochinoliny MeSH
• protein bcl-X * MeSH
• protein BCL2L11 * MeSH
• protoonkogenní proteiny c-bcl-2 MeSH
• sulfonamidy * MeSH
• venetoclax MeSH Prohlížeč

PURPOSE: Esophageal cancer (EC) is one of the most lethal gastrointestinal malignancies. Immunotherapy is a promising treatment modality for this disease. However, broader implementation of EC immunotherapy has been discouraged because of insufficient understanding of tumor interactions with the immune system. As with other malignancies, the current research on EC focuses on deciphering the immune cell signatures within the tumor microenvironment. However, the disease-elicited immune cell profiles in the paratumoral compartments are largely unknown. METHODS: We examined the immune cell signatures in 62 tissue samples from 16 EC patients in different esophageal tissue compartments: tumor tissue, peritumoral tissue, healthy esophageal tissue, and adjacent lymph nodes. We analyzed the proportions and distribution patterns of NK cells and CD4+ and CD8+ T cells as well as their death receptor (FasR, FasR/DR3)-expressing subpopulations. The analyzed data were then compared and correlated with the patients' clinicopathological data. RESULTS: We found that the FasR+ NK cells, CD4+ and CD8+ T cells infiltrated lymph nodes at the lowest levels and that the FasR+DR3+ CD4+ T cells were enhanced in tumors. The comparisons with the clinicopathological data revealed a major impact of active smoking on the reduction in paratumoral NK cells and the upregulation of FasR in tumor-infiltrating NK and CD8+ T cells. The lymph node metastatic stage, tumor stage, and Mandard grade correlated with the compartmental proportions of the evaluated immune cells. CONCLUSION: The novel association of the disease state with tumoral and paratumoral immune cell signatures suggests new possibilities for personalized immunotherapy for EC patients.

• Klíčová slova
• Death receptor 3, Esophageal cancer, Fas receptor, Mandard tumor regression grade, Peritumoral lymphocytes, Tumor-infiltrating lymphocytes,
• MeSH
• adenokarcinom imunologie   patologie   terapie   MeSH
• antigeny CD95 imunologie   MeSH
• buňky NK imunologie   patologie   MeSH
• CD4-pozitivní T-lymfocyty imunologie   patologie   MeSH
• CD8-pozitivní T-lymfocyty imunologie   patologie   MeSH
• imunoterapie metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfatické uzliny imunologie   patologie   MeSH
• lymfocyty imunologie   patologie   MeSH
• nádory jícnu imunologie   patologie   terapie   MeSH
• senioři MeSH
• skvamózní karcinom jícnu imunologie   patologie   terapie   MeSH
• studie případů a kontrol MeSH
• T-lymfocyty - podskupiny imunologie   patologie   MeSH
• tumor infiltrující lymfocyty imunologie   patologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD95 MeSH

The rationale for the use of T lymphocytes to fight cancer is the immunogenicity of tumor cells. T cells are capable to recognize and finally to kill tumor cells. Adoptive cell transfer therapies provide the opportunity to overcome tolerogenic mechanisms by enabling the selection and activation of highly reactive T cell subpopulations and by manipulation of the host environment into which the T cells are introduced. The aim of this article is to review the possibilities, limitations and recent clinical experience with this novel anticancer treatment, namely with adoptive immunotherapy using antigen-specific T cells.

• MeSH
• imunoterapie adoptivní metody   MeSH
• lidé MeSH
• nádory imunologie   chirurgie   MeSH
• T-lymfocyty imunologie   transplantace   MeSH
• tumor infiltrující lymfocyty imunologie   transplantace   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

In a limited number of human malignancies, anti-CD47 therapy leads to the rapid clearance of tumor cells by macrophages. In esophageal squamous cell carcinoma, anti-CD47 treatment has shown promising results in vitro. However, the CD47 expression pattern in tumor-infiltrating lymphocytes (TILs), which are associated with prolonged overall survival and serve as a positive prognostic factor, is largely unknown. In this study, a total of 36 tissue samples from the tumor, peritumoral tissue, and adjacent healthy esophageal tissue was obtained from 12 esophageal carcinoma (EC) patients, and the surface expression of CD47 was evaluated in natural killer (NK) cells, CD8+ T cells, and the nonlymphocyte cell fraction. We found that the proportions of the evaluated cells and their CD47-expressing populations were comparable across the analyzed tissue compartments. However, the proportions of CD47-expressing populations in the analyzed tissue compartments were significantly higher in NK cells and CD8+ T cells than in the nonlymphocyte cell fraction. Importantly, the intensity of CD47 staining was also significantly higher in the tested immune cells than in the nonlymphocyte cell fraction. High expression of CD47 in tissue-infiltrating NK cells and CD8+ T cells in EC patients can, therefore, affect the efficacy of anti-CD47 therapy in EC.

• MeSH
• antigeny CD47 genetika   metabolismus   MeSH
• buňky NK metabolismus   MeSH
• CD8-pozitivní T-lymfocyty metabolismus   MeSH
• karcinom metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory jícnu imunologie   metabolismus   MeSH
• regulace genové exprese u nádorů genetika   MeSH
• senioři MeSH
• skvamózní karcinom jícnu MeSH
• tumor infiltrující lymfocyty imunologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD47 MeSH
• CD47 protein, human MeSH Prohlížeč

Carcinogenesis in the process of long-term co-evolution of tumor cells and immune environment essentially becomes possible due to incorrect decisions made, remembered, and reproduced by the immune system at the level of clonal populations of antigen-specific T- and B-lymphocytes. Tumor-immunity interaction determines the nature of such errors and, consequently, delineates the possible ways of successful immunotherapeutic intervention. It is generally recognized that tumor-infiltrating B cells (TIL-B) can play both pro-tumor and anti-tumor roles. However, the exact mechanisms that determine the contribution of clonal B cell lineages with different specificities and functions remain largely unclear. This is due to the variability of cancer types, the molecular heterogeneity of tumor cells, and, to a large extent, the individual pattern of each immune response. Further progress requires detailed investigation of the functional properties and phenotypes of clonally heterogeneous B cells in relation to their antigenic specificities, which determine the functionality of both effector B lymphocytes and immunoglobulins produced in the tumor environment. Based on a real understanding of the role of clonal antigen-specific populations of B lymphocytes in the tumor microenvironment, we need to learn how to develop new methods of targeted immunotherapy, as well as adapt existing treatment options to the specific needs of different patients and patient subgroups. In this review, we will cover B cells functional diversity and their multifaceted roles in the tumor environment.

• Klíčová slova
• Antibody isotypes, B cell roles in cancer, Humoral response to tumor antigens,
• MeSH
• B-lymfocyty MeSH
• CD8-pozitivní T-lymfocyty * MeSH
• imunoterapie MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• nádory * terapie   metabolismus   MeSH
• tumor infiltrující lymfocyty MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH