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,
• MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• makrofágy spojené s nádory imunologie   MeSH
• nádorové mikroprostředí * imunologie   MeSH
• nádory prostaty * imunologie   patologie   terapie   MeSH
• regulační T-lymfocyty imunologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Graphene-based materials (GBMs) have shown significant promise in cancer therapy due to their unique physicochemical properties, biocompatibility, and ease of functionalization. Their ability to target solid tumors, penetrate the tumor microenvironment (TME), and act as efficient drug delivery platforms highlights their potential in nanomedicine. However, the complex and dynamic nature of the TME, characterized by metabolic heterogeneity, immune suppression, and drug resistance, poses significant challenges to effective cancer treatment. GBMs offer innovative solutions by enhancing tumor targeting, facilitating deep tissue penetration, and modulating metabolic pathways that contribute to tumor progression and immune evasion. Their functionalization with targeting ligands and biocompatible polymers improves their biosafety and specificity, while their ability to modulate immune cell interactions within the TME presents new opportunities for immunotherapy. Given the role of metabolic reprogramming in tumor survival and resistance, GBMs could be further exploited in metabolism-targeted therapies by disrupting glycolysis, mitochondrial respiration, and lipid metabolism to counteract the immunosuppressive effects of the TME. This review focuses on discussing research studies that design GBM nanocomposites with enhanced biodegradability, minimized toxicity, and improved efficacy in delivering therapeutic agents with the intention to reprogram the TME for effective anticancer therapy. Additionally, exploring the potential of GBM nanocomposites in combination with immunotherapies and metabolism-targeted treatments could lead to more effective and personalized cancer therapies. By addressing these challenges, GBMs could play a pivotal role in overcoming current limitations in cancer treatment and advancing precision oncology.

• Klíčová slova
• cancer, graphene, graphene oxide, nanomaterials, photodynamic therapy, photothermal therapy,
• MeSH
• grafit * chemie   terapeutické užití   MeSH
• imunoterapie metody   MeSH
• lékové transportní systémy metody   MeSH
• lidé MeSH
• nádorové mikroprostředí * účinky léků   MeSH
• nádory * farmakoterapie   metabolismus   MeSH
• nanokompozity * chemie   terapeutické užití   MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• grafit * MeSH
• protinádorové látky MeSH

T-cell engagers represent a transformative approach to cancer immunotherapy leveraging bispecific and multispecific antibody constructs to redirect T-cell cytotoxicity toward malignant cells. These molecules bridge T cells and tumor cells by simultaneously binding CD3 on T cells and tumor-associated antigens on cancer cells, thereby enabling precise immune targeting even in immunologically "cold" tumors. Recent advancements include conditional T-cell engagers activated by tumor microenvironment proteases to minimize off-tumor toxicity as well as T-cell receptor-based engagers targeting intracellular antigens via MHC presentation. Clinical successes, such as Kimmtrak in metastatic uveal melanoma, underscore good potential of these modalities, while challenges persist in the management of cytokine release syndrome, neurotoxicity, and tumor resistance. Emerging multispecific engagers are aimed at enhancing efficacy via incorporation of costimulatory signals, thus offering a promising trajectory for next-generation immunotherapies. T-cell engagers are also gaining attention in the treatment of autoimmune disorders, where they can be designed to selectively modulate pathogenic immune responses. By targeting autoreactive T or B cells, T-cell engagers hold promise for restoring immune tolerance in such conditions as HLA-B*27-associated autoimmunity subtypes, multiple sclerosis, rheumatoid arthritis, and type 1 diabetes mellitus. Engineering strategies that incorporate inhibitory receptors or tissue-specific antigens may further refine T-cell engagers' therapeutic potential in autoimmunity, by minimizing systemic immunosuppression while preserving immune homeostasis.

• Klíčová slova
• T-cell engager, autoimmunity, gene engineering, immunotherapy, soluble TCR,
• MeSH
• imunoterapie * metody   MeSH
• lidé MeSH
• nádorové mikroprostředí imunologie   MeSH
• nádory * imunologie   terapie   MeSH
• protilátky bispecifické terapeutické užití   imunologie   MeSH
• receptory antigenů T-buněk imunologie   metabolismus   MeSH
• T-lymfocyty * imunologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• protilátky bispecifické MeSH
• receptory antigenů T-buněk MeSH

BACKGROUND: Hormone receptor-positive (HR+) breast cancer responds poorly to immune checkpoint inhibitors (ICIs). In some settings, radiation therapy (RT) has been shown to mediate immunostimulatory effects and promote ICI sensitivity. METHODS: We investigated whether hypofractionated RT may be successfully combined with ICIs in a mouse model of multifocal, metachronous HR+ mammary carcinogenesis. We hypothesized that focal RT targeting the first detectable (primary) tumor combined with ICIs may generate effective immunity, delaying the development of new lesions. RESULTS: Focal RT in various doses and fractionations limited primary tumor growth, with an optimum for a 20-Gy × 2 regimen (ablative in approximately 90% of mice). The degree of primary disease control, however, did not necessarily correlate with overall survival extension because of changes in the development of new neoplastic lesions contributing to global tumor burden. Adding a PD-1 blocker to focal RT delivered in a 10-Gy × 3, 20-Gy × 2, or 8-Gy × 6 regimen failed to alter overall survival extension enabled by RT alone. Similar results were obtained with a CTLA4 blocker, an IL-1β inhibitor, and a PD-1 blocker plus recombinant FLT3LG when combined with the 10-Gy × 3 regimen. CONCLUSIONS: In this model of HR+ mammary carcinogenesis, RT to the primary tumor ameliorates overall survival (to an extent based on dose and fractionation). Increasing local control through RT alone or RT plus immunotherapy beyond a hitherto undefined threshold, however, does not necessarily inhibit the development of subsequent nonirradiated neoplasms and hence does not necessarily provide extra overall survival benefits.

• MeSH
• antigeny CD279 antagonisté a inhibitory   MeSH
• experimentální nádory mléčných žláz * terapie   MeSH
• frakcionace dávky záření MeSH
• hypofrakcionace při ozařování MeSH
• imunoterapie * metody   MeSH
• inhibitory kontrolních bodů * farmakologie   terapeutické užití   MeSH
• kombinovaná terapie MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádory prsu * patologie   terapie   MeSH
• receptory pro estrogeny metabolismus   MeSH
• receptory progesteronu metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD279 MeSH
• inhibitory kontrolních bodů * MeSH
• receptory pro estrogeny MeSH
• receptory progesteronu MeSH

Prostate cancer (PCa) ranks as the second leading cause of cancer-related deaths among men in the United States. Prostate-specific membrane antigen (PSMA) represents a well-established biomarker of PCa, and its levels correlate positively with the disease progression, culminating at the stage of metastatic castration-resistant prostate cancer. Due to its tissue-specific expression and cell surface localization, PSMA shows superior potential for precise imaging and therapy of PCa. Antibody-based immunotherapy targeting PSMA offers the promise of selectively engaging the host immune system with minimal off-target effects. Here we report on the design, expression, purification, and characterization of a bispecific engager, termed 5D3-CP33, that efficiently recruits macrophages to the vicinity of PSMA-positive cancer cells mediating PCa death. The engager was engineered by fusing the anti-PSMA 5D3 antibody fragment to a cyclic peptide 33 (CP33), selectively binding the Fc gamma receptor I (FcγRI/CD64) on the surface of phagocytes. Functional parts of the 5D3-CP33 engager revealed a nanomolar affinity for PSMA and FcγRI/CD64 with dissociation constants of KD = 3 nM and KD = 140 nM, respectively. At a concentration as low as 0.3 nM, the engager was found to trigger the production of reactive oxygen species by U937 monocytic cells in the presence of PSMA-positive cells. Moreover, flow cytometry analysis demonstrated antibody-dependent cell-mediated phagocytosis of PSMA-positive cancer cells by U937 monocytes when exposed to 0.15 nM 5D3-CP33. Our findings illustrate that 5D3-CP33 effectively and specifically activates monocytes upon PSMA-positive target engagement, resulting in the elimination of tumor cells. The 5D3-CP33 engager can thus serve as a promising lead for developing new immunotherapy tools for the efficient treatment of PCa.

• MeSH
• antigeny povrchové * imunologie   metabolismus   MeSH
• glutamátkarboxypeptidasa II * imunologie   metabolismus   MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• makrofágy imunologie   MeSH
• monocyty * imunologie   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory prostaty * imunologie   terapie   patologie   MeSH
• protilátky bispecifické * imunologie   farmakologie   MeSH
• receptory IgG metabolismus   imunologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny povrchové * MeSH
• FOLH1 protein, human MeSH Prohlížeč
• glutamátkarboxypeptidasa II * MeSH
• protilátky bispecifické * MeSH
• receptory IgG 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.

• Klíčová slova
• Christensenella minuta, bile acids, cancer, dendritic cells, gut microbiota, metabolomics, radiotherapy, tumor immunosurveillance,
• MeSH
• antigeny CD274 * antagonisté a inhibitory   MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• imunoterapie metody   MeSH
• inhibitory kontrolních bodů * terapeutické užití   farmakologie   MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádory * imunologie   patologie   terapie   radioterapie   farmakoterapie   MeSH
• retrospektivní studie MeSH
• střeva * účinky záření   imunologie   MeSH
• střevní mikroflóra účinky záření   imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD274 * MeSH
• CD274 protein, human MeSH Prohlížeč
• inhibitory kontrolních bodů * MeSH

Neoadjuvant immunotherapy represents a pioneering approach in the preoperative treatment of cancer, providing new strategies for tumor reduction and improved patient outcomes by modulating the immune response. This study investigated neoadjuvant immunotherapy using intratumoral administration of mannan-BAM, Toll-like receptor ligands, and anti-CD40 antibody (MBTA therapy) followed by surgery in murine models of MTT pheochromocytoma, B16-F10 melanoma, and 4T1 and E0771.lmb mammary carcinomas. In the MTT pheochromocytoma model, it was found that neoadjuvant MBTA therapy followed by surgery could prevent the development of distant metastases in 100% of treated animals, compared to a 60% mortality rate in the control group due to metastatic disease after surgery. These outcomes were achieved even in tumors three times larger than those in the control group. In the aggressive 4T1 model, neoadjuvant MBTA therapy resulted in slower tumor progression and a significant prolongation of survival. In the B16-F10 and E0771.lmb models, neoadjuvant MBTA therapy also protected animals from metastases development and tumor recurrence upon rechallenge with tumor cells after surgery. Transcriptomic analysis revealed enhanced effector immune cell infiltration, cytotoxicity, and antigen presentation in retransplanted tumors from MBTA-treated mice, indicating robust immune memory. Notably, the exclusion of the anti-CD40 antibody from the neoadjuvant MBTA therapy (MBT therapy) yielded comparable outcomes in protection against metastases development. These findings advocate for further investigation of intratumoral neoadjuvant MBTA therapy for immunologically "cold" tumors, including those at high risk of metastases or recurrence.

• Klíčová slova
• 4T1, E0771.lmb, Immunotherapy, Intratumoral, Melanoma, Neoadjuvant, Pheochromocytoma,
• MeSH
• antigeny CD40 imunologie   antagonisté a inhibitory   MeSH
• experimentální nádory mléčných žláz * imunologie   patologie   terapie   MeSH
• imunoterapie * metody   MeSH
• lokální recidiva nádoru * prevence a kontrola   imunologie   MeSH
• melanom experimentální * imunologie   terapie   patologie   sekundární   MeSH
• metastázy nádorů MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• neoadjuvantní terapie * metody   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD40 MeSH

Cancer immunotherapy is increasingly used in clinical practice, but its success rate is reduced by tumor escape from the immune system. This may be due to the genetic instability of tumor cells, which allows them to adapt to the immune response and leads to intratumoral immune heterogeneity. The study investigated spatial immune heterogeneity in the tumor microenvironment and its possible drivers in a mouse model of tumors induced by human papillomaviruses (HPV) following immunotherapy. Gene expression was determined by RNA sequencing and mutations by whole exome sequencing. A comparison of different tumor areas revealed heterogeneity in immune cell infiltration, gene expression, and mutation composition. While the mean numbers of mutations with every impact on gene expression or protein function were comparable in treated and control tumors, mutations with high or moderate impact were increased after immunotherapy. The genes mutated in treated tumors were significantly enriched in genes associated with ECM metabolism, degradation, and interactions, HPV infection and carcinogenesis, and immune processes such as antigen processing and presentation, Toll-like receptor signaling, and cytokine production. Gene expression analysis of DNA damage and repair factors revealed that immunotherapy upregulated Apobec1 and Apobec3 genes and downregulated genes related to homologous recombination and translesion synthesis. In conclusion, this study describes the intratumoral immune heterogeneity, that could lead to tumor immune escape, and suggests the potential mechanisms involved.

• Klíčová slova
• DNA repair, cancer immunotherapy, intratumoral heterogeneity, mutation, tumor microenvironment,
• MeSH
• imunoterapie * metody   MeSH
• infekce papilomavirem imunologie   virologie   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• mutace MeSH
• myši MeSH
• nádorové mikroprostředí imunologie   genetika   MeSH
• nádory * imunologie   terapie   genetika   MeSH
• regulace genové exprese u nádorů MeSH
• sekvenování exomu MeSH
• únik nádoru z imunitní kontroly genetika   imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Recurrent pregnancy loss (RPL) is defined as the occurrence of two or more consecutive pregnancy losses before 24 weeks of gestation. It affects 3-5% of women who are attempting to conceive. RPL can stem from a variety of causes and is frequently associated with psychological distress and a diminished quality of life. By contrast, recurrent implantation failure (RIF) refers to the inability to achieve a successful pregnancy after three or more high-quality embryo transfers or at least two instances of egg donation. RIF shares several causative factors with RPL. The immunological underpinnings of these conditions involve alterations in uterine NK cells, reductions in M2 macrophages and myeloid-derived suppressor cells, an increased Th1/Th2 ratio, a decreased Treg/Th17 ratio, the presence of shared ≥3 HLA alleles between partners, and autoimmune disorders. Various therapeutic approaches have been employed to address these immunological concerns, achieving varying degrees of success, although some therapies remain contentious within the medical community. This review intends to explore the immunological factors implicated in RPL and RIF and to analyze the immunological treatments employed for these conditions, which may include steroids, intravenous immunoglobulins, calcineurin inhibitors, anti-TNF antibodies, intralipid infusions, granulocyte colony-stimulating factor, and lymphocyte immunotherapy.

• Klíčová slova
• HLA, NK cells, T regulatory cells, Th1, Th17, Th2, cytokines, macrophages, recurrent implantation failure, recurrent pregnancy loss,
• MeSH
• habituální potrat * imunologie   terapie   MeSH
• implantace embrya * imunologie   MeSH
• imunoterapie metody   MeSH
• lidé MeSH
• těhotenství MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Patients with gastro-oesophageal adenocarcinoma with tumour-positive lymph nodes (ypN+) or positive surgical margins (R1) following neoadjuvant chemotherapy and resection are at high risk of recurrence. Adjuvant nivolumab is effective in oesophageal/oesophagogastric junction cancer and residual pathological disease following chemoradiation and surgery. Immune checkpoint inhibition has shown efficacy in advanced gastro-oesophageal cancer. We hypothesised that nivolumab/ipilimumab would be more effective than adjuvant chemotherapy in high-risk (ypN+ and/or R1) patients with gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and resection. PATIENTS AND METHODS: VESTIGE was an academic international, multicentre, open-label, randomised phase II trial evaluating the efficacy of adjuvant nivolumab/ipilimumab versus chemotherapy in gastro-oesophageal adenocarcinoma at high risk of recurrence. Patients were randomised 1 : 1 to receive standard adjuvant chemotherapy (same regimen as neoadjuvant) or nivolumab 3 mg/kg intravenously (i.v.) every 2 weeks plus ipilimumab 1 mg/kg i.v. every 6 weeks for 1 year. Key inclusion criteria included ypN+ and/or R1 status after neoadjuvant chemotherapy plus surgery. The primary endpoint was disease-free survival in the intent-to-treat population. Secondary endpoints included overall survival, locoregional and distant failure rates, and safety according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. RESULTS: The independent Data Monitoring Committee reviewed data from 189 of the planned 240 patients in June 2022 and recommended stopping recruitment due to futility. At the time of final analysis, median follow-up was 25.3 months for 195 patients (98 nivolumab/ipilimumab and 97 chemotherapy). Median disease-free survival for the nivolumab/ipilimumab group was 11.4 months [95% confidence interval (CI) 8.4-16.8 months] versus 20.8 months (95% CI 15.0-29.9 months) for the chemotherapy group, hazard ratio 1.55 (95% CI 1.07-2.25, one-sided P = 0.99). The 12-month disease-free survival rates were 47.1% and 64.0%, respectively. There were no toxicity concerns or excess early discontinuations. CONCLUSION: Nivolumab/ipilimumab did not improve disease-free survival compared with chemotherapy in patients with ypN+ and/or R1 gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and surgery.

• Klíčová slova
• chemotherapy, gastric cancer, immunotherapy, oesophagogastric junction cancer, perioperative,
• MeSH
• adenokarcinom * farmakoterapie   patologie   MeSH
• adjuvantní chemoterapie metody   MeSH
• dospělí MeSH
• gastroezofageální junkce * patologie   chirurgie   MeSH
• imunoterapie metody   MeSH
• ipilimumab aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru * patologie   prevence a kontrola   MeSH
• nádory jícnu * patologie   farmakoterapie   chirurgie   terapie   mortalita   MeSH
• nádory žaludku * patologie   farmakoterapie   chirurgie   terapie   mortalita   MeSH
• neoadjuvantní terapie metody   MeSH
• nivolumab aplikace a dávkování   škodlivé účinky   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• ipilimumab MeSH
• nivolumab MeSH