BACKGROUND: Immune checkpoint inhibitors (ICIs), including those targeting PD-1, are currently used in a wide range of tumors, but only 20-40% of patients achieve clinical benefit. The objective of our study was to find predictive peripheral blood-based biomarkers for ICI treatment. METHODS: In 41 patients with advanced malignant melanoma (MM) and NSCLC treated with PD-1 inhibitors, we analyzed peripheral blood-based immune subsets by flow cytometry before treatment initialization and the second therapy dose. Specifically, we assessed basic blood differential count, overall T cells and their subgroups, B cells, and myeloid-derived suppressor cells (MDSC). In detail, CD4 + and CD8 + T cells were assessed according to their subtypes, such as central memory T cells (TCM), effector memory T cells (TEM), and naïve T cells (TN). Furthermore, we also evaluated the predictive value of CD28 and ICOS/CD278 co-expression on T cells. RESULTS: Patients who achieved disease control on ICIs had a significantly lower baseline proportion of CD4 + TEM (p = 0.013) and tended to have a higher baseline proportion of CD4 + TCM (p = 0.059). ICI therapy-induced increase in Treg count (p = 0.012) and the proportion of CD4 + TN (p = 0.008) and CD28 + ICOS- T cells (p = 0.012) was associated with disease control. Patients with a high baseline proportion of CD4 + TCM and a low baseline proportion of CD4 + TEM showed significantly longer PFS (p = 0.011, HR 2.6 and p ˂ 0.001, HR 0.23, respectively) and longer OS (p = 0.002, HR 3.75 and p ˂ 0.001, HR 0.15, respectively). Before the second dose, the high proportion of CD28 + ICOS- T cells after ICI therapy initiation was significantly associated with prolonged PFS (p = 0.017, HR 2.51) and OS (p = 0.030, HR 2.69). Also, a high Treg count after 2 weeks of ICI treatment was associated with significantly prolonged PFS (p = 0.016, HR 2.33). CONCLUSION: In summary, our findings suggest that CD4 + TEM and TCM baselines and an early increase in the Treg count induced by PD-1 inhibitors and the proportion of CD28 + ICOS- T cells may be useful in predicting the response in NSCLC and MM patients.

• MeSH
• antigeny CD278 metabolismus   MeSH
• antigeny CD279 antagonisté a inhibitory   MeSH
• antigeny CD28 MeSH
• CD8-pozitivní T-lymfocyty imunologie   účinky léků   metabolismus   MeSH
• dospělí MeSH
• inhibitory kontrolních bodů * terapeutické užití   farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• melanom * farmakoterapie   imunologie   krev   patologie   MeSH
• nádory plic * farmakoterapie   imunologie   krev   patologie   MeSH
• nemalobuněčný karcinom plic * farmakoterapie   imunologie   krev   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: The IMMUNOSARC trial combined an antiangiogenic agent (sunitinib) with a PD1 inhibitor (nivolumab) in advanced sarcomas. Here, we present the first correlative studies of the soft-tissue sarcoma cohort enrolled in this trial. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded and peripheral blood samples were collected at baseline and week 13. Formalin-fixed paraffin-embedded samples were used for transcriptomics and multiplex immunofluorescence, whereas peripheral blood samples were used for multiplexed immunoassays. Flow cytometry and Luminex assays were performed to validate translational findings in tumor-isolated cells and peripheral blood mononuclear cells derived from patients. RESULTS: The density of intratumoral CD8+ T cells, measured by multiplexed immunophenotyping, was significantly increased after treatment. This augment was accompanied by the dynamic significant increase in the gene expressions of CD86, CHI3L1, CXCL10, CXCL9, LAG3, and VCAM1 and the decrease in the expression levels of NR4A1. In peripheral blood, 12 proteins were significantly modulated by treatment at week 13. A score integrating the dynamic expression of the 7 genes and the 12 soluble factors separated 2 groups with distinct progression-free survival (PFS): 4.1 months [95% confidence interval, 3.5-not reached (NR)] versus 17 months (95% confidence interval, 12.0-NR), P = 0.014. This molecular score was predictive of PFS when applied to the normalized data determined in the baseline samples. CONCLUSIONS: Treatment with sunitinib and nivolumab inflamed the sarcoma microenvironment, increasing CD8+ T-cell density and the expression of several genes/proteins with relevance in the response to PD1 inhibitors. A molecular signature identified two groups of patients with distinct PFS for the combination of antiangiogenics plus PD1 inhibitor therapy.

• MeSH
• antigeny CD279 antagonisté a inhibitory   MeSH
• CD8-pozitivní T-lymfocyty imunologie   účinky léků   metabolismus   MeSH
• dospělí MeSH
• inhibitory angiogeneze terapeutické užití   aplikace a dávkování   MeSH
• inhibitory kontrolních bodů terapeutické užití   farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery MeSH
• nádorové mikroprostředí účinky léků   imunologie   MeSH
• nivolumab terapeutické užití   aplikace a dávkování   MeSH
• prognóza MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• sarkom * farmakoterapie   patologie   genetika   MeSH
• senioři MeSH
• tumor infiltrující lymfocyty imunologie   metabolismus   účinky léků   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

CD8+ T cells are essential for adaptive immunity against infection and tumors. Their ability to proliferate after stimulation is crucial to their functionality. Dendritic cells (DCs) are professional antigen-presenting cells that induce their proliferation. Here, we show that thapsigargin-induced LAD2 mast cell (MC) line-released products can impair the ability of monocyte-derived DCs to induce CD8+ T-cell proliferation and the generation of Th1 cytokine-producing T cells. We found that culture medium conditioned with LAD2 MCs previously stimulated with thapsigargin (thapsLAD2) induces maturation of DCs as determined by the maturation markers CD80, CD83, CD86, and HLA-DR. However, thapsLAD2-matured DCs produced no detectable TNFα or IL-12 during the maturation. In addition, although their surface expression of PD-L1 was comparable with the immature or TLR7/8-agonist (R848)-matured DCs, their TIM-3 expression was significantly higher than in immature DCs and even much higher than in R848-matured DCs. In addition, contrary to R848-matured DCs, the thapsLAD2-matured DCs only tended to induce enhanced proliferation of CD4+ T cells than immature DCs. For CD8+ T cells, this tendency was not even detected because thapsLAD2-matured and immature DCs comparably induced their proliferation, which contrasted with the significantly enhanced proliferation induced by R848-matured DCs. Furthermore, these differences were comparably recapitulated in the ability of the tested DCs to induce IFNγ- and IFNγ/TNFα-producing T cells. These findings show a novel mechanism of MC-mediated regulation of adaptive immune responses.

• MeSH
• aktivace lymfocytů * účinky léků   imunologie   MeSH
• buněčná diferenciace * účinky léků   MeSH
• buněčné linie MeSH
• buněčný receptor 2 viru hepatitidy A metabolismus   MeSH
• CD8-pozitivní T-lymfocyty * imunologie   účinky léků   MeSH
• cytokiny metabolismus   MeSH
• dendritické buňky * imunologie   účinky léků   metabolismus   MeSH
• imidazoly farmakologie   MeSH
• lidé MeSH
• mastocyty * imunologie   účinky léků   metabolismus   MeSH
• monocyty imunologie   účinky léků   metabolismus   MeSH
• proliferace buněk * účinky léků   MeSH
• thapsigargin * farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Pseurotins, a family of secondary metabolites of different fungi characterized by an unusual spirocyclic furanone-lactam core, are suggested to have different biological activities including the modulation of immune response. PURPOSE: Complex characterization of the effects of pseurotin D on human lymphocyte activation in order to understand the potential of pseurotin to modulate immune response in humans. METHODS: CD4+ and CD8+ T cells and CD19+ B cells isolated from human blood were activated by various activators simultaneously with pseurotin D treatment. The effects of pseurotin were tested on the basis of changes in cell viability, apoptosis, activation of signal transducers and activators of transcription (STAT) signaling pathways, production of tumor necrosis factor (TNF)-α by T cells, expression of activation markers CD69 and CD25 on T cells and Human Leukocyte Antigen-DR isotype (HLA-DR) on B cells, and the differentiation markers CD20, CD27, CD38, and immunoglobulin (Ig) D on B cells. RESULTS: Pseurotin D significantly inhibited the activation of both CD4+ and CD8+ human T cells complemented by the inhibition of TNF-α production without significant acute toxic effects. The Pseurotin D-mediated inhibition of T-cell activation was accompanied by the induction of the apoptosis of T cells. This corresponded with the inhibited phosphorylation of STAT3 and STAT5. In human B cells, pseurotin D did not significantly inhibit their activation; however, it affected their differentiation. CONCLUSIONS: Our results advance the current mechanistic understanding of the pseurotin-induced inhibition of lymphocytes and suggest pseurotins as new attractive chemotypes for future research in the context of immune-modulatory drugs.

• MeSH
• aktivace lymfocytů účinky léků   MeSH
• antigeny CD19 metabolismus   MeSH
• apoptóza účinky léků   MeSH
• B-lymfocyty účinky léků   imunologie   MeSH
• buněčná diferenciace účinky léků   MeSH
• CD4-pozitivní T-lymfocyty účinky léků   imunologie   MeSH
• CD8-pozitivní T-lymfocyty účinky léků   imunologie   MeSH
• dospělí MeSH
• imunologické faktory farmakologie   MeSH
• kultivované buňky MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• pyrrolidinony farmakologie   MeSH
• signální transdukce účinky léků   MeSH
• TNF-alfa metabolismus   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• CD8-pozitivní T-lymfocyty účinky léků   MeSH
• folikulární lymfom * diagnóza   terapie   MeSH
• imunosupresivní léčba škodlivé účinky   MeSH
• lidé MeSH
• senioři MeSH
• syndromy imunologické nedostatečnosti * chemicky indukované   terapie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

BACKGROUND: A high multiple sclerosis activity while on alemtuzumab is rather uncommon compared to moderate-efficacy drugs. The purpose of this case report is to present a case of a 37-year-old female patient with bronchial asthma and no other medical history, whose disease activity required switching from dimethyl fumarate to fingolimod, then to alemtuzumab and finally to ocrelizumab. CASE PRESENTATION: In our patient, two severe attacks were observed and treated after administration of the first pulse of alemtuzumab. After six months of therapy, patient's immunological profile showed the expected decrease in CD4+ and CD8+ T-cells and, markedly increased values of CD19+ B-cells. Surprisingly memory B-cells, which typically repopulate very slowly following alemtuzumab treatment, were above baseline levels. Regular administration of ocrelizumab based on a standardised scheme, after the alemtuzumab therapy failure, resulted in the stabilisation of the patient's condition both clinically and radiologically. CONCLUSION: Thus, when the alemtuzumab treatment is unsuccessful, the authors recommend testing T- and B-cell levels and proceeding with an early switch to ocrelizumab if high B-cell counts are found.

• MeSH
• alemtuzumab terapeutické užití   MeSH
• B-lymfocyty účinky léků   MeSH
• CD4-pozitivní T-lymfocyty účinky léků   MeSH
• CD8-pozitivní T-lymfocyty účinky léků   MeSH
• dospělí MeSH
• humanizované monoklonální protilátky terapeutické užití   MeSH
• lidé MeSH
• relabující-remitující roztroušená skleróza farmakoterapie   MeSH
• terapie neúspěšná * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Význam tumor infiltrujících lymfocytů (tumor-infiltrating lymphocytes, TIL) a jejich vztah k prognóze nemocných byl rozsáhle studován u celé řady malignit. Výsledky metaanalýz poukazují především na pozitivní vliv lymfocytární infiltrace na celkovou dobu přežití a též na možnost predikce odpovědi na léčbu imunoterapií u pacientů se stanovenou denzitou lymfocytárního infiltrátu v nádoru. Nejde však jen o zastoupení buněk, ale i o jejich funkční vlastnosti vyjádřené expresí povrchových i intracelulárních znaků. Potenciál TIL je zřejmý. Podaří-li se vytvoření jednotných guidelines pro měření a interpretaci TIL v nádoru, získáme účinný nástroj pro rozhodování v rámci terapeutického algoritmu.

The role of the tumor-infiltrating lymphocytes (TIL) and its relationship to prognosis has been extensively studied in multiple cancers. Systematic reviews and meta-analysis have shown a positive correlation between the lymphocyte infiltration and the overall survival (OS) and also have revealed the possibility of predicting therapeutic response to immunotherapy by evaluating the lymphocyte density in the tumor. However, the presence of tumor infiltrating lymphocytes must be described together with the functional features and the phenotypic patterns of the cells. The potential of TIL is evident and therefore, establishing systematic guidelines for evaluation and interpretation of TIL may provide a powerful tool in predicting the survival of the patient and selecting an optimal therapeutic approach.

• MeSH
• buňky NK klasifikace   účinky léků   MeSH
• CD8-pozitivní T-lymfocyty * klasifikace   účinky léků   MeSH
• imunoterapie metody   trendy   MeSH
• kolorektální nádory klasifikace   prevence a kontrola   MeSH
• lidé MeSH
• melanom klasifikace   prevence a kontrola   MeSH
• metaanalýza jako téma MeSH
• nádory jater klasifikace   prevence a kontrola   MeSH
• nádory prsu klasifikace   prevence a kontrola   MeSH
• nádory vaječníků klasifikace   prevence a kontrola   MeSH
• nádory žaludku klasifikace   prevence a kontrola   MeSH
• prognóza * MeSH
• tumor infiltrující lymfocyty * klasifikace   účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Small molecule Toll-like receptor-7 and -8 agonists (TLR-7/8a) can be used as vaccine adjuvants to induce CD8 T cell immunity but require formulations that prevent systemic toxicity and focus adjuvant activity in lymphoid tissues. Here, we covalently attached TLR-7/8a to polymers of varying composition, chain architecture and hydrodynamic behavior (∼300 nm submicrometer particles, ∼10 nm micelles and ∼4 nm flexible random coils) and evaluated how these parameters of polymer-TLR-7/8a conjugates impact adjuvant activity in vivo. Attachment of TLR-7/8a to any of the polymer compositions resulted in a nearly 10-fold reduction in systemic cytokines (toxicity). Moreover, both lymph node cytokine production and the magnitude of CD8 T cells induced against protein antigen increased with increasing polymer-TLR-7/8a hydrodynamic radius, with the submicrometer particle inducing the highest magnitude responses. Notably, CD8 T cell responses induced by polymer-TLR-7/8a were dependent on CCR2+ monocytes and IL-12, whereas responses by a small molecule TLR-7/8a that unexpectedly persisted in vaccine-site draining lymph nodes (T1/2 = 15 h) had less dependence on monocytes and IL-12 but required Type I IFNs. This study shows how modular properties of synthetic adjuvants can be chemically programmed to alter immunity in vivo through distinct immunological mechanisms.

• MeSH
• adjuvancia imunologická aplikace a dávkování   chemie   farmakologie   MeSH
• aktivace lymfocytů * MeSH
• buněčné linie MeSH
• CD8-pozitivní T-lymfocyty účinky léků   imunologie   MeSH
• cytokiny metabolismus   MeSH
• hydrodynamika MeSH
• kultivované buňky MeSH
• micely * MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• toll-like receptor 7 agonisté   MeSH
• toll-like receptor 8 agonisté   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH

Increasing evidence suggests that antibody-drug conjugates (ADCs) can enhance anti-tumor immunity and improve clinical outcome. Here, we elucidate the therapeutic efficacy and immune-mediated mechanisms of a novel HER2-targeting ADC bearing a potent anthracycline derivate as payload (T-PNU) in a human HER2-expressing syngeneic breast cancer model resistant to trastuzumab and ado-trastuzumab emtansine. Mechanistically, the anthracycline component of the novel ADC induced immunogenic cell death leading to exposure and secretion of danger-associated molecular signals. RNA sequencing derived immunogenomic signatures and TCRβ clonotype analysis of tumor-infiltrating lymphocytes revealed a prominent role of the adaptive immune system in the regulation of T-PNU mediated anti-cancer activity. Depletion of CD8 T cells severely reduced T-PNU efficacy, thus confirming the role of cytotoxic T cells as drivers of the T-PNU mediated anti-tumor immune response. Furthermore, T-PNU therapy promoted immunological memory formation in tumor-bearing animals protecting those from tumor rechallenge. Finally, the combination of T-PNU and checkpoint inhibition, such as α-PD1, significantly enhanced tumor eradication following the treatment. In summary, a novel PNU-armed, HER2-targeting ADC elicited long-lasting immune protection in a murine orthotopic breast cancer model resistant to other HER2-directed therapies. Our findings delineate the therapeutic potential of this novel ADC payload and support its clinical development for breast cancer patients and potentially other HER2 expressing malignancies.

• MeSH
• antigeny CD279 antagonisté a inhibitory   MeSH
• antracykliny terapeutické užití   MeSH
• CD8-pozitivní T-lymfocyty účinky léků   imunologie   MeSH
• experimentální nádory mléčných žláz farmakoterapie   imunologie   MeSH
• imunokonjugáty terapeutické užití   MeSH
• imunologická paměť účinky léků   MeSH
• lidé MeSH
• myši inbrední BALB C MeSH
• nádorové buněčné linie MeSH
• protinádorové látky imunologicky aktivní terapeutické užití   MeSH
• receptor erbB-2 antagonisté a inhibitory   genetika   MeSH
• trastuzumab terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Chronická benigní CD8+ proliferace je vzácná afekce, jež může napodobovat řadu jiných onemocnění. Klinicky se manifestuje cytopeniemi nebo infiltrací lymfatických uzlin, jater, ledvin, střeva, či jiných orgánů. CD8+ expanze může být neklonální i klonální a vyskytuje se zpravidla u pacientů s vrozeným nebo získaným imunodeficitem (HIV+) nebo u pacientů léčených imunosupresivní léčbou. Byla také zaznamenána u pacientů po podání protilátky anti-CD20 (rituximabu). Diagnostika bývá obtížná, klinický i laboratorní obraz může věrně napodobit progresi lymfomu. Standardně vyšetřená biopsie uzliny pomůže sice vyloučit relaps lymfomu, avšak tuto poruchu na první pohled nemusí odhalit. Popisujeme případ pacientky v remisi folikulárního lymfomu předléčené rituximabem. Pro podezření na systémový relaps lymfomu (lymfadenopatie, subfebrilie, elevace jaterních enzymů) byla provedena biopsie patologické uzliny, která však v odebrané uzlině zachytila pouze nekrotizující lymfadenitidu. V laboratorním nálezu byla zachycena nově agamaglobulinemie. Flowcytometrické vyšetření odhalilo patologickou populaci CD8+ lymfocytů v krvi, kostní dřeni a následně i v uzlině. Léčba, která se zásadně liší od léčby relapsu lymfomu, spočívá v podání kortikoidů a důsledné substituce intravenózními imunoglobuliny (IVIG), vedla k regresi klinických i laboratorních symptomů. S častějším podáváním rituximabu lze očekávat i stoupající výskyt této doposud velmi vzácné afekce.

Chronic benign CD8+ proliferation is a rare affection that can mimic a variety of other diseases. It clinically manifests as cytopenia or infiltration of lymph nodes, liver, kidneys, the bowel and other organs. CD8+ expansion can be clonal or non-clonal and generally occurs in patients with innate or acquired immunodeficiency (HIV+) or in patients on immunosuppressive treatment. It has also been detected in patients following rituximab (anti-CD 20 antibody) treatment. The diagnosis can be difficult a standard biopsy may not identify the problem at first sight. We describe the case of a patient with lymphoma in remission pre-treated with rituximab, who was suspected of systemic relapse of her lymphoma (lymphadenopathy, fever, liver enzymes elevation). Biopsy of an enlarged lymph node showed “reactive lymphadenitis”. Flow cytometry revealed a pathological population of CD8+ lymphocytes. The treatment, quite different from that of lymphoma relapse, consisted of corticosteroids and regular IVIG administration led to regression of all clinical and laboratory signs. As rituximab is used more and more frequently, we can expect an increased incidence of this entity.

• Klíčová slova
• chronická CD8+ lymfoproliferace,
• MeSH
• CD8-pozitivní T-lymfocyty účinky léků   MeSH
• chronická nemoc MeSH
• diferenciální diagnóza MeSH
• folikulární lymfom * terapie   MeSH
• imunoglobuliny aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• lymfoproliferativní nemoci * diagnóza   farmakoterapie   chemicky indukované   patologie   MeSH
• prednison terapeutické užití   MeSH
• rituximab * škodlivé účinky   terapeutické užití   MeSH
• senioři MeSH
• udržovací chemoterapie MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH