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
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 protinádorové 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
- Názvy látek
- antigeny CD279 MeSH
- inhibitory angiogeneze MeSH
- inhibitory kontrolních bodů MeSH
- nádorové biomarkery MeSH
- nivolumab MeSH
- PDCD1 protein, human MeSH Prohlížeč
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
BACKGROUND: We aimed to assess the prognostic value of tumor infiltrating lymphocytes (TILs) in patients with bladder cancer (BC) after radical cystectomy (RC). MATERIALS AND METHODS: We searched Pubmed, Web of Science and Scopus in April 2022 to identify studies assessing the prognostic value of TILs, including a subset of lymphocytes (eg, CD3, CD8, FOXP3), after RC. The endpoints were overall survival and recurrent free survival. Subgroup analyses were performed based on the evaluation method for TILs (ie, CD3, CD8, FOXP3, HE staining). RESULTS: Overall, 9 studies comprising 1413 patients were included in this meta-analysis. The meta-analysis revealed that elevated expressions of TILs were significantly associated with favorable OS (pooled hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.51-0.83) and RFS (pooled HR: 0.48, 95% CI: 0.35-0.64). In subgroup analyses, high CD8+ TILs were also associated with favorable OS (HR: 0.51, 95% CI: 0.33-0.80) and RFS (pooled HR: 0.53, 95% CI: 0.36-0.76). Among 3 studies comprising 146 patients, high intratumoral TILs were significantly associated with favorable OS (pooled HR: 0.34, 95% CI: 0.19-0.60). CONCLUSION: TILs are useful prognostic markers in patients treated with RC for BC. Although the prognostic value of TILs is varied, depending on the subset and infiltration site, CD8+ TILs and intratumoral TILs are associated with oncologic outcomes. Further studies are warranted to explicate the predictive value of TILs on the response to perioperative systemic therapy to help clinical decision-making in patients with BC.
- Klíčová slova
- MIBC, TIL,
- MeSH
- cystektomie MeSH
- forkhead transkripční faktory metabolismus MeSH
- lidé MeSH
- nádory močového měchýře * patologie MeSH
- prognóza MeSH
- tumor infiltrující lymfocyty * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
- systematický přehled MeSH
- Názvy látek
- forkhead transkripční faktory MeSH
BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.
- Klíčová slova
- fibrotic focus, lymphovascular invasion, prognostic biomarkers, stromal tumor-infiltrating lymphocytes, triple-negative breast cancer,
- MeSH
- adjuvantní chemoterapie MeSH
- lidé MeSH
- nádorové biomarkery MeSH
- prognóza MeSH
- triple-negativní karcinom prsu * farmakoterapie patologie MeSH
- tumor infiltrující lymfocyty metabolismus patologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- nádorové biomarkery MeSH
BACKGROUND: Immunotherapy blocking the PD-1/PD-L1 signalling pathway has become a dominant treatment modality for patients with non-small cell lung carcinoma (NSCLC). Programmed death-ligand 1 (PD-L1) expression on the membrane of tumour cells and/or tumour infiltrating lymphocytes (TIL) evaluated immunohistochemically is still the only clinically validated predictive biomarker for immunotherapy, but it has its limitations. TIL in the tumour microenviroment was identified as having predictive value. We retrospectively evaluated 134 NSCLC resection specimens, and analysed the association between PD-L1 expression, the presence of TIL, and the degree of desmoplasia in tumours. MATERIAL AND METHODS: PD-L1 expression on tumour cells and TIL were evaluated immunohistochemically using the anti-PD-L1 antibody (clone 22C3) and the anti-CD3 antibody (polyclone), respectively. PD-L1 was scored using the “tumour proportion score” (TPS) system with three categories: TPS < 1%, 1-49%, and 50%. TIL were evaluated semiquantitatively using the “percentage of stromal TIL” (PST) system, and categories of PST < 10%, 10-49% and 50% were recorded. The association between PD-L1 expression in tumour cells and TIL was compared with the PST value. Statistical analysis was conducted using the Cochran-Armitage test, and a p-value < 5% was considered significant. RESULTS: PD-L1 expression was significantly higher in PST 10-49% and 50% categories than in the PST < 10% category in grade 1 and grade 2 adenocarcinomas (p = 0.008), grade 3 adenocarcinomas (p = 0.009), and squamous cell carcinomas (p = 0.028). PD-L1 expression in TIL was associated with the PST value in squamous cell carcinomas (p = 0.025) but not in adenocarcinomas. Desmoplastic tumours had particularly low TPS and PST values. CONCLUSION: PD-L1 expression in NSCLC is associated with the presence of TIL. Desmoplastic areas in tumours represent immunologically inactive tumour microenviroments. Administration of anti-PD-1/PD-L1 immunotherapy, together with agents blocking the TGF-β signalling pathway, represent a promising combinational therapy for patients with desmoplastic NSCLC. The authors declare they have no potential confl cts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 25. 11. 2019 Accepted: 8. 12. 2019.
- Klíčová slova
- non-small cell lung carcinoma, predictive biomarker, programmed death-ligand 1, tumour infiltrating lymphocytes,
- MeSH
- adenokarcinom metabolismus MeSH
- antigeny CD274 metabolismus MeSH
- biopsie MeSH
- lidé MeSH
- nádory plic metabolismus patologie MeSH
- nemalobuněčný karcinom plic metabolismus patologie MeSH
- stupeň nádoru MeSH
- tumor infiltrující lymfocyty metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antigeny CD274 MeSH
- CD274 protein, human MeSH Prohlížeč
- Klíčová slova
- Adenoid cystic carcinoma, CD8 T cells, Checkpoint inhibitors, Fas ligand, Granzyme, PD-L1, Salivary gland carcinoma, Tumor microenvironment, Tumor-infiltrating lymphocytes,
- MeSH
- adenoidně cystický karcinom metabolismus MeSH
- antigeny CD95 metabolismus MeSH
- lidé MeSH
- ligand Fas metabolismus MeSH
- nádorové mikroprostředí fyziologie MeSH
- nádory slinných žláz metabolismus MeSH
- slinné žlázy metabolismus MeSH
- tumor infiltrující lymfocyty metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- Názvy látek
- antigeny CD95 MeSH
- FAS protein, human MeSH Prohlížeč
- FASLG protein, human MeSH Prohlížeč
- ligand Fas MeSH
OBJECTIVES: Renal cell carcinoma (RCC) is the most lethal urologic malignancy with increasing incidence worldwide. The conventional treatment strategies for advanced or recurrent RCC are not efficient and show considerable toxicities. Adoptive cell transfer (ACT) has become a promising treatment option for multiple cancers, particularly in combination with other therapeutic approaches. ACT often utilizes extensively in vitro expanded tumor-infiltrating lymphocytes (TILs). However, TILs are a very heterogeneous mix of cell populations and only those populations that have a cytotoxic and migratory potential are thought to deliver a therapeutic impact in ACT. The identification and localization of these therapeutically potent populations are therefore needed. METHODS AND MATERIALS: A total number of 57 tissue samples from 19 RCC patients who underwent radical nephrectomy was analyzed. The tissue samples were obtained from the tumor, peritumoral tissue, and the adjacent healthy renal tissue. The tissues were sliced, enzymatically dissociated into single cell suspensions and the obtained cells further analyzed by flow cytometry for the expression of markers of lymphocyte cytotoxicity - TRAIL and FasL, and a surrogate marker of lymphocyte migratory activity - PECAM-1. The analyzed data were next correlated with the clinical and histopathological data. RESULTS: Non-clear cell RCC (non-ccRCC) tumors showed a significantly decreased tumor infiltration with TRAIL+FasL+ NK cells but elevated infiltration with FasL+PECAM-1+ T cells as compared with clear cell RCC (ccRCC) tumors. Further analyses revealed that the peritumoral tissue of ccRCC patients is a reservoir of TRAIL+FasL+, TRAIL+PECAM-1+, or FasL+PECAM-1+ NK and T cells. CONCLUSIONS: The cytotoxic/migratory lymphocytes were identified in tumors of ccRCC patients. These lymphocytes became excluded from the tumor and accumulated in the patient's peritumoral tissue.
- Klíčová slova
- FasL, PECAM-1, Renal cell carcinoma, TRAIL, Tumor-infiltrating lymphocytes, peritumoral,
- MeSH
- antigeny CD31 metabolismus MeSH
- buňky NK imunologie metabolismus MeSH
- cytotoxicita imunologická MeSH
- karcinom z renálních buněk imunologie patologie chirurgie MeSH
- ledviny cytologie imunologie patologie chirurgie MeSH
- lidé středního věku MeSH
- lidé MeSH
- ligand Fas metabolismus MeSH
- nádory ledvin imunologie patologie chirurgie MeSH
- nefrektomie MeSH
- protein TRAIL metabolismus MeSH
- průtoková cytometrie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- separace buněk MeSH
- T-lymfocyty imunologie metabolismus MeSH
- tumor infiltrující lymfocyty imunologie metabolismus MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antigeny CD31 MeSH
- FASLG protein, human MeSH Prohlížeč
- ligand Fas MeSH
- PECAM1 protein, human MeSH Prohlížeč
- protein TRAIL MeSH
- TNFSF10 protein, human MeSH Prohlížeč
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
BACKGROUND: Despite recent advances in the therapy for adenocarcinoma of the esophagogastric junction (AEG), overall prognosis remains poor. Programmed cell death protein 1 (PD1) is a co-inhibitory receptor primarily expressed by T-cells. Tumor cells can escape anticancer immune responses by triggering the PD1 pathway. Moreover, PD1 receptor engagement on cancer cells may trigger tumor-intrinsic growth signals. This study aimed to evaluate the potential clinical relevance of PD1 expression by tumor-infiltrating lymphocytes (TILs) and cancer cells in the AEG. METHODS: Patients with AEG who underwent esophagectomy from 1992 to 2011 were included in the study. Expression of PD1was evaluated by immunohistochemistry and correlated with long-term overall survival (OS), disease-free survival (DFS), and various clinicopathologic parameters. RESULTS: Tumor biospecimens from 168 patients were analyzed. In the analysis, 81% of the patients showed high tumoral frequencies (>5%) of PD1-expressing TILs (TIL-PD1+), and 77% of patient tumors harbored high levels (>5%) of PD1+ cancer cells (cancer-PD1+). Expression of PD1 by TILs and cancer cells correlated significantly (p < 0.05) with patients' tumor stage and lymph node involvement. Compared with the patients who had low tumoral frequencies of PD1+ TILs or cancer cells, the TIL-PD1+ and cancer-PD1+ patients demonstrated significantly reduced DFS in the univariate analysis (5-year DFS: 73.3 vs. 41.9%, log-rank 0.008 and 71.3 vs. 41.6%, p = 0.008, respectively). Additionally, the cancer-PD1+ patients showed significantly decreased OS in the univariate analysis compared with the cancer-PD1- patients (5-year OS: 68.8 vs. 43.5%; p = 0.047). However, these correlations did not reach significance in the multivariate analysis. CONCLUSIONS: The PD1 receptor is expressed by both TILs and cancer cells in AEG. High expression of PD1 is associated with advanced tumor stage and lymph node involvement, but not with survival.
- MeSH
- adenokarcinom metabolismus sekundární chirurgie MeSH
- antigeny CD279 metabolismus MeSH
- dospělí MeSH
- gastroezofageální junkce * MeSH
- imunohistochemie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfatické metastázy MeSH
- míra přežití MeSH
- nádory jícnu metabolismus patologie chirurgie MeSH
- přežití bez známek nemoci MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- staging nádorů MeSH
- tumor infiltrující lymfocyty metabolismus 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
- Názvy látek
- antigeny CD279 MeSH
- PDCD1 protein, human MeSH Prohlížeč