INTRODUCTION: The E3 ubiquitin ligase Cbl-b is a novel target in immune-oncology, with critical roles in regulating T-cell activation and signaling pathways. By facilitating the ubiquitination and degradation of key signaling proteins, Cbl-b modulates immune responses, maintaining immune homeostasis and preventing unwarranted T-cell proliferation. The therapeutic potential of Cbl-b as a cancer immunotherapy target is underscored by its contribution to an immunosuppressive tumor microenvironment, with efforts currently underway to develop small-molecule inhibitors. AREAS COVERED: We reviewed the small molecules, and antibody-drug conjugates targeting Cbl-b from 2018 to 2024. The patents were gathered through publicly available databases and analyzed with in-house developed cheminformatic workflow, described within the manuscript. EXPERT OPINION: Targeting Cbl-b presents a promising approach in immuno-oncology, offering a novel pathway to potentiate the immune system's ability to combat cancer beyond PDL1/PD1 inhibition. The development and clinical advancement of Cbl-b inhibitors, as evidenced by the ongoing trials, mark a significant step toward harnessing this target for therapeutic benefits. Overall, the strategic inhibition of Cbl-b holds substantial promise for improving cancer immunotherapy outcomes, heralding a new era in the fight against cancer.

• MeSH
• adaptorové proteiny signální transdukční MeSH
• cílená molekulární terapie * MeSH
• imunokonjugáty farmakologie   MeSH
• imunoterapie * metody   MeSH
• lidé MeSH
• nádorové mikroprostředí * imunologie   MeSH
• nádory * imunologie   farmakoterapie   MeSH
• patenty jako téma * MeSH
• protinádorové látky farmakologie   MeSH
• protoonkogenní proteiny c-cbl * imunologie   antagonisté a inhibitory   MeSH
• signální transdukce účinky léků   MeSH
• T-lymfocyty imunologie   účinky léků   MeSH
• vyvíjení léků * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Prognostic value of T-cells between primary colorectal cancer (pCRC) and its paired synchronous and metachronous liver metastasis (LM) is underinvestigated and is the subject of the present study. We enrolled into this retrospective cohort study patients, who underwent resection of both pCRC and synchronous LM (N = 55) or metachronous LM (N = 44). After immunohistochemical staining for CD3+, CD8+, and CD45R0+ whole slides were scanned and T-cell densities were quantified using QuPath software in tumor center (TC), inner margin (IM), outer margin (OM), and peritumor zone (PT) of pCRC and LM. High densities of CD8+ T-cells in TC, OM and PT of synchronous LM were associated with longer disease-free survival (DFS). Greater densities of CD3+ T-cells in IM and PT and CD8+ T-cells in IM, OM and PT in synchronous LM over pCRC were associated with longer DFS. Greater densities of CD8+ T-cells in the TC and IM and CD3+ T-cells in the IM of pCRC were found in the metachronous over synchronous group. The first novel finding demonstrated that high density of CD8+ T cells in synchronous LM were associated with favorable outcome. The second finding of high CD8+ cell density in pCRC in metachronous over synchronous CRC may provide a mechanistic basis for the delay of metastatic spread. Both findings could be applied clinically with own reference values.

• MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• dospělí MeSH
• kolorektální nádory * patologie   imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetné primární nádory patologie   imunologie   MeSH
• nádory jater * sekundární   imunologie   patologie   MeSH
• přežití bez známek nemoci MeSH
• prognóza MeSH
• retrospektivní studie MeSH
• sekundární malignity patologie   MeSH
• senioři MeSH
• T-lymfocyty imunologie   patologie   MeSH
• tumor infiltrující lymfocyty imunologie   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Immunotherapy represents a revolutionary advancement in cancer treatment, which has traditionally focused on T cells; however, the role of B cells in cancer immunotherapy has gained interest because of their role in antigen presentation, antibody production, and cytokine release. In this study, we examined the role of B cells in previously developed intratumoral MBTA therapy (mannan-BAM, TLR ligands, and anti-CD40 antibody) in murine models of MTT pheochromocytoma. The results indicated that B cells significantly enhance the success of MBTA therapy, with wild-type mice exhibiting a lower tumor incidence and smaller tumors compared with B cell-deficient mice. Increased IL-6 and TNF-alpha levels indicated severe inflammation and a potential cytokine storm in B cell-deficient mice. Neutralization of TNF-alpha ameliorated these complications but resulted in increased tumor recurrence. The results highlight the important role of B cells in enhancing the immune response and maintaining immune homeostasis during MBTA therapy. Our findings offer new insights into improving therapeutic outcomes.

• MeSH
• B-lymfocyty * imunologie   MeSH
• feochromocytom * imunologie   terapie   MeSH
• imunoterapie * metody   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádory nadledvin * imunologie   terapie   MeSH
• TNF-alfa MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Intramural MeSH

Our aim is to determine the number of leukocytes, T lymphocytes and B lymphocytes and the expression of activation markers CD200 and CD23 on B lymphocytes in atopic dermatitis (AD) patients (treated and not treated with dupilumab) during the pollen season. We examined 29 patients not treated with dupilumab, 24 patients treated with dupilumab and 40 healthy subjects as a control group. The count of T and B lymphocytes and their subsets were assessed by flow cytometry. The non-parametric Kruskal-Wallis one-factor analysis of variance with post hoc by Dunn's test with Bonferroni's modification was used for statistical processing. Although there was a significant improvement in skin findings in patients treated with dupilumab, the changes in immunological profile show a persistent altered immune response characterized by dysregulation and overactivation of B lymphocytes. Dupilumab therapy leads to normalization of relative T regulatory lymphocytes and total memory B lymphocytes and to decreased count of absolute CD8+ T lymphocytes. Why carry out this study?Studies investigating the immunological profile of atopic dermatitis (AD) patients during the pollen season are rare. There are no studies investigating the count of B lymphocytes (CD5+, CD22+ and CD73+ B lymphocytes) and the expression of activation markers CD23 and CD200 on B lymphocytes and on their subsets during pollen season in AD patients treated and non-treated with dupilumab therapy.What was learned from the study?In atopic dermatitis (AD) patients with and without dupilumab therapy, we confirmed the significantly higher count of absolute neutrophils, absolute monocytes, absolute eosinophils, absolute basophils, non-switched B lymphocytes, transitional B lymphocytes, CD23 memory, naive, non-switched, switched and total CD23 B lymphocytes, the relative count of CD200 memory and CD200 switched B lymphocytes.In dupilumab treated patients, we confirmed the significantly higher count of relative eosinophils, relative CD16+ eosinophils, relative CD200 non-switched B lymphocytes and lower count of absolute CD8+ T lymphocytes. Further studies should focus on investigating the effect of dupilumab on CD8+ T lymphocytes and their subpopulations.In patients without dupilumab therapy, we confirmed the significantly higher count of relative neutrophils, relative T regulatory lymphocytes and total memory B lymphocytes.The changes in the count of CD5+, CD22+ and CD73+ B lymphocytes were not observed during pollen season in both groups of AD patients.

• MeSH
• atopická dermatitida * farmakoterapie   imunologie   MeSH
• B-lymfocyty imunologie   MeSH
• CD antigeny MeSH
• dospělí MeSH
• humanizované monoklonální protilátky * terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• pyl imunologie   MeSH
• receptory IgE MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. To examine this question, we studied genome-wide microarray results from 5086 kidney transplant biopsies (from 4170 patients). An updated molecular archetypal analysis designated 56% of biopsies as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower estimated glomerular filtration rate, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR, respectively, diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems.

• MeSH
• biopsie MeSH
• dospělí MeSH
• hodnoty glomerulární filtrace MeSH
• isoprotilátky imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• přežívání štěpu imunologie   MeSH
• prognóza MeSH
• rejekce štěpu * patologie   imunologie   etiologie   MeSH
• rizikové faktory MeSH
• T-lymfocyty imunologie   MeSH
• transplantace ledvin * škodlivé účinky   MeSH
• vyšetření funkce ledvin MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Numerous studies have reported that increased interleukin 6 (IL-6) and soluble IL-6 receptor (sIL-6) levels induce inflammatory conditions. However, the exact mechanisms by which IL-6 drives inflammatory conditions remain unclear. Therefore, we investigated the potential role of IL-6/sIL-6R in inducing energy metabolism, including glycolysis, oxidative phosphorylation, lactate secretion and Akt/mTOR phosphorylation, in Jurkat cells, and whether IL-6 would increase the risk of developing inflammatory conditions due to the high metabolic profile of the T cells. Jurkat CD4 T-cell lines were stimulated with IL-6/sIL-6R for 24 h prior to 48-h stimulation with anti-CD3/CD28. Lactate secretion, glycolysis and oxidative phosphorylation levels were characterized using the Seahorse XF analyser. The Akt and mTOR phosphorylation status was detected using Western blotting. IL-6/sIL-6R significantly induced glycolysis and oxidative phosphorylation and their related parameters, including glycolytic capacity and maximal respiration, followed by significantly increased lactate secretion. Akt and mTOR phosphorylation were increased, which could have resulted from energy metabolism. Here we show that IL-6 enhanced the metabolic profile of Jurkat cells. This effect could have consequences for the metabolism-related signalling pathways, including Akt and mTOR, suggesting that IL-6 might promote T-cell energy metabolism, where T-cell hyperactivity might increase the inflammatory disease risk. The findings should be validated using studies on primary cells isolated from humans.

• MeSH
• energetický metabolismus * účinky léků   MeSH
• fosforylace účinky léků   MeSH
• glykolýza účinky léků   MeSH
• interleukin-6 * metabolismus   MeSH
• Jurkat buňky MeSH
• kyselina mléčná metabolismus   MeSH
• lidé MeSH
• oxidativní fosforylace účinky léků   MeSH
• protoonkogenní proteiny c-akt * metabolismus   MeSH
• signální transdukce * účinky léků   MeSH
• TOR serin-threoninkinasy * metabolismus   MeSH
• zánět * metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Úvod a cíl studie: Uterinní NK (uNK) buňky jsou specializovanou subpopulací NK (natural killer) lymfocytů nacházejících se v endometriu. Hrají klíčovou roli v regulaci imunitní odpovědi a v procesu implantace embrya. Cílem této studie je retrospektivní analýza výsledků léčby metodou in vitro fertilizace (IVF) v souboru žen, které podstoupily imunofenotypizaci uNK buněk a na základě výsledků tohoto vyšetření byly, nebo nebyly léčeny imunomodulační terapií. Metody: Studie zahrnovala 122 pacientek, které podstoupily imunofenotypizaci uNK buněk v období od dubna do prosince 2023. Imunofenotypizace byla provedena metodou průtokové cytometrie. Pacientky byly roztříděny do čtyř skupin dle fenotypu uNK buněk: normální nálezy, nízké absolutní a relativní počty uNK (LOW-IMMUNE profil), nízké počty uNK v kombinaci s nežádoucím posunem směrem k cytotoxickému uNKdim imunofenotypu (MIXED-IMMUNE profil) a normální počty uNK, ale nežádoucí posun v poměru cytotoxických a regulačních uNK s cytotoxickým fenotypem (OVER-IMMUNE profil). Byly hodnoceny výsledky embryotransferu a výskyt potratů do ukončeného 12. týdne těhotenství v jednotlivých skupinách. Výsledky: Nejvyšší míra dosažení klinické gravidity byla nalezena v léčené skupině OVER- -IMMUNE (70 %), následované skupinou MIXED-IMMUNE (60 %). Skupina LOW-IMMUNE se od neléčené NORMAL skupiny signifikantně nelišila (p = 0,205). Nedostatečná imunitní aktivace (LOW-IMMUNE profil) byla signifikantně nejčastěji sdružena s prvotrimestrální těhotenskou ztrátou (p < 0,0001). Závěr: Tato studie přináší nové poznatky o potenciálu imunofenotypizace uNK buněk a následné imunomodulační terapie v léčbě poruch plodnosti. Ačkoli výsledky naznačují možné klinické přínosy, je zapotřebí dalšího výzkumu k potvrzení těchto zjištění a k objasnění mechanizmů, které vedou ke zlepšení výsledků léčby technikami asistované reprodukce.

Introduction and objective: Uterine NK (uNK) cells, a specialized subpopulation of natural killer (NK) lymphocytes located in the endometrium, play a crucial role in regulating the immune response and in the process of embryo implantation. This study aims to retrospectively analyze the outcomes of in vitro fertilization (IVF) treatment in a cohort of women who underwent uNK cell immunophenotyping with subsequent immunomodulatory therapy applied based on the results. Methods: The study included 122 patients who underwent uNK cell immunophenotyping between April and December 2023. Immunophenotyping was performed using flow cytometry. Patients were categorized into four groups according to their uNK cell phenotypes: normal findings, low absolute and relative numbers of uNK cells (LOW-IMMUNE profile), low numbers of uNK cells combined with the shift towards the cytotoxic uNKc dim immunophenotype (MIXED-IMMUNE profile), and normal numbers of uNK cells, but an undesirable shift in the ratio of cytotoxic to regulatory uNK cells towards the cytotoxic uNK dim phenotype (OVER-IMMUNE profile). Embryo transfer outcomes and the occurrence of miscarriages up to the 12th week of pregnancy were evaluated in each group. Results: The highest clinical pregnancy rate was observed in the treated OVER-IMMUNE group (70%), fol lowed by the MIXED-IMMUNE group (60%). The LOW-IMMUNE group did not differ significantly from the untreated NORMAL group (P = 0.205). Insufficient immune activation (LOW-IMMUNE profile) was significantly associated with first-trimester pregnancy loss (P < 0.0001). Conclusion: This study provides new insights into the potential benefits of uNK cell immunophenotyping and subsequent immunomodulatory therapy in treating fertility disorders. While the results indicate possible clinical advantages, further research is necessary to confirm these findings and elucidate the mechanisms leading to improved outcomes in assisted reproductive techniques.

• Klíčová slova
• uterinní NK buňky, imunofenotypizace lymfocytů, opakované selhání implantace,
• MeSH
• buňky NK MeSH
• endometrium cytologie   MeSH
• fertilizace in vitro * MeSH
• habituální potrat MeSH
• imunofenotypizace MeSH
• imunomodulace MeSH
• lidé MeSH
• průtoková cytometrie metody   MeSH
• retrospektivní studie MeSH
• ženská infertilita * MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH

AIMS: This study aimed to examine changes in the repertoire of functional T-cells specific for six leukemia-associated antigens (LAA), including WT1, PRAME, MUC1, CCNA1, NPM1, and NPM1c, during immune reconstitution following allogeneic transplantation of hematopoietic stem cells (HSCT) in patients with acute myeloid leukemia. PATIENTS & METHODS: LAA-specific T cell response was measured by ELISPOT- IFNγ and intracellular cytokine staining in 47 patients before starting conditioning therapy (baseline) and 7 months after HSCT. RESULTS: The positive cumulative LAA-specific T cell response before HSCT was associated with a decreased risk of relapse after HSCT. The prevalent genetic aberration - an internal tandem duplication of Fms 3 - related receptor tyrosine kinase, which has been previously implicated in immune escape mechanisms, is presented here for the first time as a factor associated with the absence of an adaptive T cell response against multiple LAAs. T-cell specific responses against wild-type and mutated NPM1 antigens were less frequent in the study cohort and did not correlate with mutations in the NPM1 gene. CONCLUSIONS: Our results showed that the T-cell response to LAA can be reconstituted after HSCT. Measurement of functional pre-transplant T-cell responses against multiple LAAs could help to find patients with an increased risk of relapse.

• MeSH
• akutní myeloidní leukemie * terapie   imunologie   genetika   MeSH
• antigeny nádorové imunologie   MeSH
• dospělí MeSH
• homologní transplantace MeSH
• jaderné proteiny genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mucin 1 genetika   imunologie   MeSH
• mutace * MeSH
• nukleofosmin * MeSH
• proteiny WT1 imunologie   genetika   MeSH
• recidiva MeSH
• senioři MeSH
• T-lymfocyty * imunologie   MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• tyrosinkinasa 3 podobná fms * genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Nonspecific structural chromosomal aberrations (CAs) are found in around 1% of circulating lymphocytes from healthy individuals but the frequency may be higher after exposure to carcinogenic chemicals or radiation. CAs have been used in the monitoring of persons exposed to genotoxic agents and radiation. Previous studies on occupationally exposed individuals have shown associations between the frequency of CAs in peripheral blood lymphocytes and subsequent cancer risk. The cause for CA formation is believed to be unrepaired or insufficiently repaired DNA double-strand breaks or other DNA damage, and additionally telomere shortening. CAs include chromosome (CSAs) and chromatid type aberrations (CTAs). In the present review, we first describe the types of CAs, the conventional techniques used for their detection and some aspects of interpreting the results. We then focus on germline genetic variation in the frequency and type of CAs measured in a genome-wide association study in healthy individuals in relation to occupational and smoking-related exposure compared to nonexposed referents. The associations (at P < 10-5) on 1473 healthy individuals were broadly classified in candidate genes from functional pathways related to DNA damage response/repair, including PSMA1, UBR5, RRM2B, PMS2P4, STAG3L4, BOD1, COPRS, and FTO; another group included genes related to apoptosis, cell proliferation, angiogenesis, and tumorigenesis, COPB1, NR2C1, COPRS, RHOT1, ITGB3, SYK, and SEMA6A; a third small group mapped to genes KLF7, SEMA5A and ITGB3 which were related to autistic traits, known to manifest frequent CAs. Dedicated studies on 153 DNA repair genes showed associations for some 30 genes, the expression of which could be modified by the implicated variants. We finally point out that monitoring of CAs is so far the only method of assessing cancer risk in healthy human populations, and the use of the technology should be made more attractive by developing automated performance steps and incorporating artificial intelligence methods into the scoring.

• MeSH
• celogenomová asociační studie * MeSH
• chromozomální aberace * MeSH
• interakce genů a prostředí MeSH
• lidé MeSH
• lymfocyty metabolismus   MeSH
• nádory genetika   MeSH
• oprava DNA genetika   MeSH
• poškození DNA MeSH
• pracovní expozice škodlivé účinky   MeSH
• vystavení vlivu životního prostředí škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an open conundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefits of immune checkpoint inhibitors or chemotherapy in eight retrospective cohorts of cancer patients and in tumor-bearing mice. The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and on the metabolic and immune host-microbiota interaction at baseline allowing CD8+ T cell activation without exhaustion. Various strains of Christensenella minuta selectively boost the anti-cancer efficacy of ILDR and PD-L1 blockade, allowing emigration of intestinal PD-L1-expressing dendritic cells to tumor-draining lymph nodes. An interventional phase 2 study provides the proof-of-concept that ILDR can circumvent resistance to first- or second-line immunotherapy in cancer patients. Prospective clinical trials are warranted to define optimal dosimetry and indications for ILDR to maximize its therapeutic potential.

• MeSH
• antigeny CD274 * antagonisté a inhibitory   metabolismus   imunologie   MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• imunoterapie metody   MeSH
• inhibitory kontrolních bodů * farmakologie   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádory imunologie   radioterapie   terapie   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• střeva patologie   účinky záření   MeSH
• střevní mikroflóra MeSH
• zvířata MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH