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1.
Int J Clin Oncol ; 29(8): 1152-1160, 2024 Aug.
Article de Anglais | MEDLINE | ID: mdl-38896182

RÉSUMÉ

BACKGROUND: The association between p16INK4a and p21, a marker of cellular senescence, and the Immunoscore, an immunological prognostic indicator, in rectal cancer patients undergoing curative surgery were investigated. METHODS: A total of 82 patients who underwent curative surgery for rectal cancer were evaluated. The resected specimens were analyzed for p16INK4a, p21, CD3 and CD8 expression by immunohistochemistry. Immunoscore was calculated on the basis of CD3 and CD8 expressions. The clinicopathological characteristics and long-term outcomes were evaluated. RESULTS: Among the 82 patients, 24 (29.3%) were p16INK4a-positive and 11 (13.4%) were p21-positive. The patients were classified into the following five Immunoscore groups (IS0-5). IS0, IS1 and IS2 were classified as the low Immunoscore group (45 patients, 54.9%) and IS3 and IS4 as the high Immunoscore group (37 patients, 45.1%). There was no significant difference in age, sex, body mass index, American Society of Anesthesiologists physical status, depth of invasion of the tumor, lymph node metastasis and histological classification of the tumor with p16INK4a or p21 expression or Immunoscore. p16INK4a-positive expression and low Immunoscore each showed a tendency to indicate poor prognosis of disease-free survival (DFS). Patients with the combination of p16INK4a and p21 positivity and with p16INK4a positivity and low Immunoscore showed significantly poor prognosis of DFS. Patients with p21 positive positivity and low Immunoscore tended to have worse DFS. CONCLUSIONS: p16INK4a, p21 and Immunoscore may be prognostic indicators of rectal cancer. The combination of them may provide more accurate prognostic prediction than either factor alone.


Sujet(s)
Marqueurs biologiques tumoraux , Inhibiteur p16 de kinase cycline-dépendante , Inhibiteur p21 de kinase cycline-dépendante , Tumeurs du rectum , Humains , Mâle , Tumeurs du rectum/anatomopathologie , Tumeurs du rectum/immunologie , Tumeurs du rectum/chirurgie , Femelle , Sujet âgé , Adulte d'âge moyen , Pronostic , Adulte , Sujet âgé de 80 ans ou plus , Survie sans rechute , Antigènes CD3/métabolisme , Antigènes CD8/analyse , Immunohistochimie
2.
Clin Exp Med ; 24(1): 99, 2024 May 15.
Article de Anglais | MEDLINE | ID: mdl-38748269

RÉSUMÉ

Current clinical guidelines limit surgical intervention to patients with cT1-2N0M0 small cell lung cancer (SCLC). Our objective was to reassess the role of surgery in SCLC management, and explore novel prognostic indicators for surgically resected SCLC. We reviewed all patients diagnosed with SCLC from January 2011 to April 2021 in our institution. Survival analysis was conducted using the Kaplan-Meier method, and independent prognostic factors were assessed through the Cox proportional hazard model. In addition, immunohistochemistry (IHC) staining was performed to evaluate the predictive value of selected indicators in the prognosis of surgically resected SCLC patients. In the study, 177 SCLC patients undergoing surgical resection were ultimately included. Both univariate and multivariate Cox analysis revealed that incomplete postoperative adjuvant therapy emerged as an independent risk factor for adverse prognosis (p < 0.001, HR 2.96). Survival analysis revealed significantly superior survival among pN0-1 patients compared to pN2 patients (p < 0.0001). No significant difference in postoperative survival was observed between pN1 and pN0 patients (p = 0.062). Patients with postoperative stable disease (SD) exhibited lower levels of tumor inflammatory cells (TIC) (p = 0.0047) and IFN-γ expression in both area and intensity (p < 0.0001 and 0.0091, respectively) compared to those with postoperative progressive disease (PD). Conversely, patients with postoperative SD showed elevated levels of stromal inflammatory cells (SIC) (p = 0.0453) and increased counts of CD3+ and CD8+ cells (p = 0.0262 and 0.0330, respectively). Survival analysis indicated that high levels of SIC, along with low levels of IFN-γ+ cell area within tumor tissue, may correlate positively with improved prognosis in surgically resected SCLC (p = 0.017 and 0.012, respectively). In conclusion, the present study revealed that the patients with pT1-2N1M0 staging were a potential subgroup of SCLC patients who may benefit from surgery. Complete postoperative adjuvant therapy remains an independent factor promoting a better prognosis for SCLC patients undergoing surgical resection. Moreover, CD3, CD8, IFN-γ, TIC, and SIC may serve as potential indicators for predicting the prognosis of surgically resected SCLC.


Sujet(s)
Antigènes CD3 , Immunohistochimie , Interféron gamma , Tumeurs du poumon , Carcinome pulmonaire à petites cellules , Humains , Mâle , Femelle , Études rétrospectives , Adulte d'âge moyen , Pronostic , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/chirurgie , Tumeurs du poumon/mortalité , Interféron gamma/métabolisme , Sujet âgé , Carcinome pulmonaire à petites cellules/chirurgie , Carcinome pulmonaire à petites cellules/anatomopathologie , Carcinome pulmonaire à petites cellules/mortalité , Carcinome pulmonaire à petites cellules/métabolisme , Antigènes CD3/métabolisme , Antigènes CD8/métabolisme , Antigènes CD8/analyse , Adulte , Marqueurs biologiques tumoraux/analyse , Analyse de survie , Sujet âgé de 80 ans ou plus , Estimation de Kaplan-Meier , Cellules stromales/anatomopathologie , Cellules stromales/métabolisme
3.
J Hematol Oncol ; 15(1): 11, 2022 01 24.
Article de Anglais | MEDLINE | ID: mdl-35073937

RÉSUMÉ

Limited previous studies focused on the death and progression risk stratification of colorectal cancer (CRC) lung metastasis patients. The aim of this study is to construct a nomogram model combing machine learning-pathomics, radiomics features, Immunoscore and clinical factors to predict the postoperative outcome of CRC patients with lung metastasis. In this study, a total of 103 CRC patients having metastases limited to lung and undergoing radical lung resection were identified. Patch-level convolutional neural network training in weakly supervised manner was used to perform whole slides histopathological images survival analysis. Synthetic minority oversampling technique and support vector machine classifier were used to identify radiomics features and build predictive signature. The Immunoscore for each patient was calculated from the density of CD3+ and CD8+ cells at the invasive margin and the center of metastatic tumor which were assessed on consecutive sections of automated digital pathology. Finally, pathomics and radiomics signatures were successfully developed to predict the overall survival (OS) and disease free survival (DFS) of patients. The predicted pathomics and radiomics scores are negatively correlated with Immunoscore and they are three independent prognostic factors for OS and DFS prediction. The combined nomogram showed outstanding performance in predicting OS (AUC = 0.860) and DFS (AUC = 0.875). The calibration curve and decision curve analysis demonstrated the considerable clinical usefulness of the combined nomogram. Taken together, the developed nomogram model consisting of machine learning-pathomics signature, radiomics signature, Immunoscore and clinical features could be reliable in predicting postoperative OS and DFS of colorectal lung metastasis patients.


Sujet(s)
Tumeurs colorectales/anatomopathologie , Tumeurs du poumon/secondaire , Antigènes CD3/analyse , Antigènes CD8/analyse , Tumeurs colorectales/diagnostic , Apprentissage profond , Femelle , Humains , Tumeurs du poumon/diagnostic , Mâle , Nomogrammes
4.
J Neuroimmunol ; 360: 577720, 2021 11 15.
Article de Anglais | MEDLINE | ID: mdl-34543880

RÉSUMÉ

It is well documented that sporadic Alzheimer's disease (AD) is a multifactorial disease and considered to be a result of several pathological events, both in the periphery and in the brain. The role of the peripheral immune system in the etiology and/or progression of the disease is not fully understood yet, and the results in humans are contradictory so far. Several animal models of AD have been generated and thoroughly characterized to elucidate disease mechanisms and evaluate numerous therapeutic strategies in preclinical studies. In the present study, we carried out a longitudinal evaluation of blood lymphocytes from male and female 3xTg-AD mice to document important immunological abnormalities in the periphery. We documented the age-dependent decrease in the percentage of CD3+ and CD4+ lymphocytes and an increase in the percentage CD3+CD4-CD8- (DN T) cells in the blood of 3xTg-AD mice compared with non-transgenic animals. Severe splenomegaly was observed in 3xTg-AD mice in contrast to wild-type animals. Importantly, all these abnormalities in the peripheral immune system appeared earlier and were more pronounced in males compared with females of the same age, which may account for the shorter lifespan of male mice. We suggest that future research should include the measurement of CD3+ and DN T cells as a potential immunological marker of disease progression in AD patients.


Sujet(s)
Vieillissement/immunologie , Maladie d'Alzheimer/immunologie , Numération des lymphocytes , Caractères sexuels , Sous-populations de lymphocytes T/immunologie , Vieillissement/sang , Maladie d'Alzheimer/sang , Animaux , Antigènes CD3/analyse , Antigènes CD4/analyse , Antigènes CD8/analyse , Modèles animaux de maladie humaine , Évolution de la maladie , Femelle , Humains , Mâle , Souris , Souris transgéniques , Sous-populations de lymphocytes T/composition chimique
5.
Int J Mol Sci ; 22(17)2021 Sep 06.
Article de Anglais | MEDLINE | ID: mdl-34502561

RÉSUMÉ

Immunoprofiling has an established impact on the prognosis of several cancers; however, its role and definition in high-grade serous ovarian cancer (HGSOC) are mostly unknown. This study is to investigate immunoprofiling which could be a prognostic factor in HGSOC. We produced tumor microarrays of 187 patients diagnosed with HGSOC. We performed a multiplexed immunofluorescence staining using Opal Multiplex IHC kit and quantitative analysis with Vectra-Inform system. The expression intensities of programmed death-ligand 1 (PD-L1), CD4, CD8, CD20, FoxP3, and CK in whole tumor tissues were evaluated. The enrolled patients showed general characteristics, mostly FIGO stage III/IV and responsive to chemotherapy. Each immune marker showed diverse positive densities, and each tumor sample represented its immune characteristics as an inflamed tumor or noninflamed tumor. No marker was associated with survival as a single one. Interestingly, high ratios of CD8 to FoxP3 and CD8 to PD-L1 were related to the favorable overall survival (77 vs. 39 months, 84 vs. 47 months, respectively), and CD8 to PD-L1 ratio was also a significant prognostic factor (HR 0.621, 95% CI 0.420-0.917, p = 0.017) along with well-known clinical prognostic factors. Additionally, CD8 to PD-L1 ratio was found to be higher in the chemosensitive group (p = 0.034). In conclusion, the relative expression levels of CD8, FoxP3, and PD-L1 were significantly related to the clinical outcome of patients with HGSOC, which could be a kind of significant immunoprofiling of ovarian cancer patients to apply for treatment.


Sujet(s)
Marqueurs biologiques tumoraux/analyse , Cystadénocarcinome séreux/métabolisme , Technique d'immunofluorescence/méthodes , Tumeurs de l'ovaire/métabolisme , Coloration et marquage/méthodes , Adulte , Sujet âgé , Antigène CD274/analyse , Antigènes CD8/analyse , Cystadénocarcinome séreux/diagnostic , Femelle , Facteurs de transcription Forkhead/analyse , Humains , Adulte d'âge moyen , Analyse multifactorielle , Grading des tumeurs , Tumeurs de l'ovaire/diagnostic , Pronostic , Analyse de survie
6.
J Histochem Cytochem ; 69(9): 611-615, 2021 09.
Article de Anglais | MEDLINE | ID: mdl-34353148

RÉSUMÉ

With the advent of checkpoint inhibitors, there is increasing need to study the dynamics of CD8+ T-cells in the tumor microenviroment. In this article, we describe a semi-automated method to quantify and interrogate spatial relationships between T-cells and collagenous stroma in human and mouse tissue samples. The assay combines CD8 immunohistochemistry with modified Masson's trichrome. Slides are scanned and digital images are analyzed using an adjustable MATLAB algorithm, allowing for high-throughput quantification of cytotoxic T-cells and collagen. This method provides a flexible tool for unbiased quantification of T-cells and their interactions with tumor cells and tumor microenvironment in tissue samples.


Sujet(s)
Antigènes CD8/analyse , Tests de criblage à haut débit , Algorithmes , Animaux , Humains , Immunohistochimie , Souris , Microenvironnement tumoral
7.
Clin Exp Immunol ; 205(3): 406-416, 2021 09.
Article de Anglais | MEDLINE | ID: mdl-34107064

RÉSUMÉ

Sarcoidosis is a multi-systemic granulomatous disease of unknown origin. Recent research has focused upon the role of autoimmunity in its development and progression. This study aimed to determine and define the disturbance and distribution of T and B cell subsets in the alveolar and peripheral compartments. Thirteen patients were selected for the study [median age, interquartile range (IQR) = 57 years (48-59); 23% were male]. Twelve healthy controls [median age, IQR = 53 years (52-65); 16% male] were also enrolled into the study. Cellular and cytokine patterns were measured using the cytofluorimetric approach. Peripheral CD8 percentages were higher in sarcoidosis patients (SP) than healthy controls (HC) (p = 0.0293), while CD4 percentages were lower (p = 0.0305). SP showed low bronchoalveolar lavage (BAL) percentages of CD19 (p = 0.0004) and CD8 (p = 0.0035), while CD19+ CD5+ CD27- percentages were higher (p = 0.0213); the same was found for CD4 (p = 0.0396), follicular regulatory T cells (Treg ) (p = 0.0078) and Treg (p < 0.0001) cells. Low T helper type 17 (Th17) percentages were observed in BAL (p = 0.0063) of SP. Peripheral CD4+ C-X-C chemokine receptor (CXCR)5+ CD45RA- ) percentages and follicular T helper cells (Tfh)-like Th1 (Tfh1) percentages (p = 0.0493 and p = 0.0305, respectively) were higher in the SP than HC. Tfh1 percentages and Tfh-like Th2 percentages were lower in BAL than in peripheral blood (p = 0.0370 and p = 0.0078, respectively), while CD4+ C-X-C motif CXCR5+ CD45RA- percentages were higher (p = 0.0011). This is the first study, to our knowledge, to demonstrate a link between an imbalance in circulating and alveolar Tfh cells, especially CCR4-, CXCR3- and CXCR5-expressing Tfh subsets in the development of sarcoidosis. These findings raise questions about the pathogenesis of sarcoidosis and may provide new directions for future clinical studies and treatment strategies.


Sujet(s)
Immunité acquise/immunologie , Sous-populations de lymphocytes B/immunologie , Sarcoïdose pulmonaire/immunologie , Lymphocytes T auxiliaires/immunologie , Lymphocytes T régulateurs/immunologie , Sujet âgé , Auto-immunité/immunologie , Liquide de lavage bronchoalvéolaire/composition chimique , Antigènes CD8/analyse , Cytokines/sang , Femelle , Humains , Mâle , Adulte d'âge moyen
8.
Science ; 372(6547)2021 06 11.
Article de Anglais | MEDLINE | ID: mdl-34112666

RÉSUMÉ

Next-generation tissue-based biomarkers for immunotherapy will likely include the simultaneous analysis of multiple cell types and their spatial interactions, as well as distinct expression patterns of immunoregulatory molecules. Here, we introduce a comprehensive platform for multispectral imaging and mapping of multiple parameters in tumor tissue sections with high-fidelity single-cell resolution. Image analysis and data handling components were drawn from the field of astronomy. Using this "AstroPath" whole-slide platform and only six markers, we identified key features in pretreatment melanoma specimens that predicted response to anti-programmed cell death-1 (PD-1)-based therapy, including CD163+PD-L1- myeloid cells and CD8+FoxP3+PD-1low/mid T cells. These features were combined to stratify long-term survival after anti-PD-1 blockade. This signature was validated in an independent cohort of patients with melanoma from a different institution.


Sujet(s)
Antinéoplasiques immunologiques/usage thérapeutique , Marqueurs biologiques tumoraux/analyse , Technique d'immunofluorescence , Mélanome/traitement médicamenteux , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Antigènes CD/analyse , Antigènes de différenciation des myélomonocytes/analyse , Antigène CD274/analyse , Antigènes CD8/analyse , Femelle , Facteurs de transcription Forkhead/analyse , Humains , Protéines de points de contrôle immunitaires/analyse , Macrophages/composition chimique , Mâle , Mélanome/composition chimique , Mélanome/immunologie , Mélanome/anatomopathologie , Adulte d'âge moyen , Pronostic , Récepteur-1 de mort cellulaire programmée/analyse , Survie sans progression , Récepteurs de surface cellulaire/analyse , Facteurs de transcription SOX-E/analyse , Analyse sur cellule unique , Sous-populations de lymphocytes T/composition chimique , Sous-populations de lymphocytes T/immunologie , Résultat thérapeutique , Microenvironnement tumoral
9.
Ginekol Pol ; 92(5): 344-351, 2021.
Article de Anglais | MEDLINE | ID: mdl-33914317

RÉSUMÉ

OBJECTIVES: Ovarian cancer is a heterogeneous disease, where chronic inflammation plays a key role in carcinogenesis. In this study, it is aimed to analyze the relationship with prognosis and chemotherapy response to clinicopathologicalnvariables in epithelial ovarian cancers such as proliferation of PD-1 +, CD8 +, CD4 +, CD3 + T-lymphocytes infiltrating the tumor and tumor stroma. MATERIAL AND METHODS: Seventy-six cases diagnosed with primary epithelial ovarian tumor from biopsy or surgical resection materials were included in the study. Immunreactivity of CD3, CD4, CD8, PD1 was evaluated immunohistochemically in lymphocytes in tumor infiltrating lymphocytes and stromal lymphocytes. RESULTS: Seventeen (22.4%) of the cases were Type I, 59 (77.6%) of them were Type II ovarian carcinoma. PD-1 positivity was observed in stromal and intraepithelial lymphocytes in 22 (28.9%) of 76 cases. In the presence of PD-1 + T-lymphocytes that infiltrate tumor and stroma, disease-free survival are shorter (p = 0.037). The presence of stromal CD4 + and CD8 + T-lymphocytes was more common in late stage patients (p = 0.012, p = 0.036; respectively). The disease-free and overall survival rate was statistically significantly shorter in the presence of CD8 + T lymphocytes (p = 0.009, p = 0.003; respectively). CONCLUSIONS: CD3, CD4 and CD8 may contribute to PD-1 mediated tumor control. Anti PD-1 therapy may be an alternative to chemotherapy in PD-1 positive patients. Identifying patients who do not respond to chemotherapy through PD-1 expression prior to immunotherapy will help develop potential personalized immunotherapy.


Sujet(s)
Carcinome épithélial de l'ovaire , Lymphocytes TIL , Tumeurs de l'ovaire , Récepteur-1 de mort cellulaire programmée , Antigènes CD3/analyse , Antigènes CD3/métabolisme , Antigènes CD4/analyse , Antigènes CD4/métabolisme , Antigènes CD8/analyse , Antigènes CD8/métabolisme , Lymphocytes T CD8+/métabolisme , Lymphocytes T CD8+/anatomopathologie , Carcinome épithélial de l'ovaire/diagnostic , Carcinome épithélial de l'ovaire/thérapie , Femelle , Humains , Immunothérapie , Lymphocytes TIL/composition chimique , Lymphocytes TIL/métabolisme , Tumeurs de l'ovaire/diagnostic , Tumeurs de l'ovaire/thérapie , Pronostic , Récepteur-1 de mort cellulaire programmée/analyse , Récepteur-1 de mort cellulaire programmée/métabolisme
11.
Int J Hematol ; 113(5): 723-734, 2021 May.
Article de Anglais | MEDLINE | ID: mdl-33502734

RÉSUMÉ

Wilms' tumor 1 (WT1) is a tumor-associated antigen and immunotherapy target in myelodysplastic syndrome (MDS). Further information is needed on the characteristics of WT1-specific CD8 + T cells to develop immunotherapeutic strategies for MDS. To clarify the frequency, distribution, and phenotype of WT1-specific CD8 + T cells, which occur innately in MDS patients, we analyzed paired peripheral blood (PB) and bone marrow (BM) samples from 39 patients with MDS or acute myeloid leukemia with myelodysplasia-related changes. The median frequency of WT1 tetramer-binding CD8 + T cells in the CD8 + T cell population was 0.11% in PB and 0.18% in BM. A further tetramer assay combined with mixed lymphocyte peptide culture (MLPC assay) was used to detect functional WT1-specific CD8 + T cells that could respond to the WT1 peptide. Functional WT1-specific CD8 + T cells were detected in BM in 61% of patients, which was significantly higher than in PB (23%, p = 0.001). The frequency of these cells estimated by the MLPC assay was tenfold higher in BM than in PB. The majority of WT1 tetramer-binding CD8 + T cells in BM had a unique phenotype with co-expression of CD39 and CXCR4. These findings will facilitate the development of novel immunotherapeutic strategies for MDS.


Sujet(s)
Moelle osseuse/immunologie , Antigènes CD8/analyse , Syndromes myélodysplasiques/immunologie , Lymphocytes T cytotoxiques/immunologie , Protéines WT1/analyse , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Antigènes CD8/immunologie , Humains , Adulte d'âge moyen , Protéines WT1/immunologie
12.
J Pathol Clin Res ; 7(1): 42-51, 2021 01.
Article de Anglais | MEDLINE | ID: mdl-32885920

RÉSUMÉ

Automatic quantification of biomarkers such as tumor-infiltrating lymphocytes and PD-L1 is one of the most studied topics in digital pathology image analysis (DIA). However, direct comparison between the DIA of a whole-slide image (WSI) and that of regions of interest (ROIs) chosen by pathologists has not been performed. In this study, we aimed to compare the prognostic value of tumor microenvironment markers CD8 and PD-L1, measured by DIA of WSIs and ROIs. We selected 153 primary gastric cancer tissues and stained them with CD8 and PD-L1. All IHC slides were scanned at ×200 magnification and ratios of CD8 and PD-L1 were measured in WSIs and ROIs from the invasive front, within the tumor, and the mucosa. Patients with high CD8 and PD-L1 ratios showed more favorable outcomes compared to those with low ratios. Pathologist-aided DIA predicted the survival of patients more accurately than WSI analysis (CD8, p = 0.025 versus p = 0.068; PD-L1, p = 0.008 versus p = 0.2). Although a high density of CD8+ T cells at the invasive front correlated best with patient survival, CD8 ratio in the mucosa could also predict patient outcome. In conclusion, CD8 and PD-L1 ratios measured by pathologist-aided DIA predicted survival more accurately than WSI analyses and ROIs at the invasive front correlated best with patient outcome.


Sujet(s)
Adénocarcinome/immunologie , Antigène CD274/analyse , Marqueurs biologiques tumoraux/analyse , Antigènes CD8/analyse , Lymphocytes T CD8+/immunologie , Interprétation d'images assistée par ordinateur , Immunohistochimie , Lymphocytes TIL/immunologie , Microscopie , Anatomopathologistes , Tumeurs de l'estomac/immunologie , Adénocarcinome/mortalité , Adénocarcinome/anatomopathologie , Adénocarcinome/chirurgie , Laboratoire automatique , Survie sans rechute , Gastrectomie , Humains , Numération des lymphocytes , Valeur prédictive des tests , Reproductibilité des résultats , Tumeurs de l'estomac/mortalité , Tumeurs de l'estomac/anatomopathologie , Tumeurs de l'estomac/chirurgie , Microenvironnement tumoral
13.
Histopathology ; 78(7): 1009-1018, 2021 Jun.
Article de Anglais | MEDLINE | ID: mdl-33340423

RÉSUMÉ

AIM: Tumour budding ('attacker') and CD8+ T cells ('defender') are recognised as important parameters for risk stratification in colon cancers and, combined, may have an even stronger clinical impact. Here, we determine the value of tumour budding and CD8+ in rectal cancer patients treated with/without neoadjuvant therapy. METHODS AND RESULTS: Using digital scans of all tumour slides/case, we analysed CD8+ T cell counts in two patient cohorts: 45 neoadjuvantly treated and 47 primarily surgically treated (totalling n = 543 slides) after double-staining of the surgical resection specimen for pan-cytokeratin and CD8+ . Tumour buds in hot-spots were manually counted (area = 0.785 mm2 ) and CD8+ T cell counts were analysed separately both in tumour budding hot-spots and the densest CD8+ regions throughout the tumour. In neoadjuvantly treated patients, only tumour budding and not CD8+ T cells was associated with tumour features, including more advanced ypT (P = 0.0062), venous invasion (P = 0.002), lymphatic invasion (P = 0.0003) and perineural invasion (P = 0.0017), as well as higher American Joint Committee on Cancer (AJCC) tumour regression score (P = 0.0035), indicating less tumour response. Overall survival was also worse in patients with high-grade budding in univariate analysis only. In contrast, all three variables, namely tumour budding (P = 0.0347), CD8+ T cells in budding hot-spots (P = 0.0382) and CD8+ T cells in the densest areas (P = 0.0117) were also associated with worse (budding) and better (CD8) survival time in the multivariate setting. CONCLUSION: In rectal cancer, tumour budding has clinical relevance in both primarily surgically treated patients and in those with neoadjuvantly treated patients, where it characterises highly aggressive residual disease. CD8+ T cell counts appear not to have prognostic relevance in the neoadjuvant context.


Sujet(s)
Lymphocytes T CD8+ , Traitement néoadjuvant , Tumeurs du rectum , Antigènes CD8/analyse , Lymphocytes T CD8+/métabolisme , Lymphocytes T CD8+/anatomopathologie , Tumeurs du côlon/imagerie diagnostique , Tumeurs du côlon/traitement médicamenteux , Tumeurs du côlon/anatomopathologie , Traitement médicamenteux , Femelle , Humains , Immunohistochimie , Kératines/analyse , Mâle , Stadification tumorale , Pronostic , Tumeurs du rectum/imagerie diagnostique , Tumeurs du rectum/traitement médicamenteux , Tumeurs du rectum/anatomopathologie
14.
Int Immunopharmacol ; 90: 107144, 2021 Jan.
Article de Anglais | MEDLINE | ID: mdl-33187907

RÉSUMÉ

Metastasis commonly occurs in colorectal cancer (CRC) patients and confers a poor prognosis. B7-H4, an immune checkpoint molecule, has been found to be expressed in numerous tumor tissues and play critical roles in tumor progression. However, B7-H4 expression and its prognostic significance in different metastases from CRC remain unclear. In the present study, we screened a novel mouse anti-human B7-H4 monoclonal antibody (mAb) which exhibited a higher degree of recognition and sensitivity than the commercial reagent in immunohistochemistry (IHC). Using this antibody, overall 110 metastatic and paired primary lesions of CRC were analyzed for their expression of B7-H4, CD8 and CD68. Our results showed that expression of B7-H4 and CD68 in metastastic lesions was significantly higher than that in matched primary lesions (P = 0.0016, P < 0.0001). We also found a significant increase of CD68-positive immune cell infiltration in the B7-H4 high expressing metastases (P = 0.041). Moreover, upregulated B7-H4 in metastatic lesions was correlated with poor prognosis of patients (P = 0.014), while in primary lesions, B7-H4 combined with CD8 was associated with the overall survival (OS) (P = 0.043). Further, B7-H4 expression in metastatic lesions was significantly correlated with hazard ratio (HR) both in univariate and multivariate analysis. Altogether, B7-H4 in metastatic lesions is promising to be a potential prognostic indicator of CRC, and may promote tumor progression and metastasis of this cancer.


Sujet(s)
Marqueurs biologiques tumoraux/analyse , Tumeurs colorectales/composition chimique , V-set domain-containing T-cell activation inhibitor 1/analyse , Sujet âgé , Animaux , Antigènes CD/analyse , Antigènes de différenciation des myélomonocytes/analyse , Antigènes CD8/analyse , Cellules CHO , Tumeurs colorectales/immunologie , Tumeurs colorectales/mortalité , Tumeurs colorectales/anatomopathologie , Cricetulus , Évolution de la maladie , Femelle , Humains , Immunohistochimie , Mâle , Souris de lignée BALB C , Adulte d'âge moyen , Métastase tumorale , Valeur prédictive des tests , Pronostic , Microenvironnement tumoral , Régulation positive
15.
PLoS One ; 15(11): e0242572, 2020.
Article de Anglais | MEDLINE | ID: mdl-33237936

RÉSUMÉ

Cluster of differentiation 4 (CD4) molecule expressed on the leukocytes is known to function as a co-receptor for class II major histocompatibility complex (MHC) binding to T cell receptor (TCR) on helper T cells. We previously identified two CD4 alleles (CD4.A and CD4.B) in a Microminipig population based on nucleotide sequencing and PCR detection of their gene sequences. However, CD4.B protein expression was not examined because of the unavailability of a reactive antibody to a CD4.B epitope. In this study, we have produced two swine-specific monoclonal antibodies (mAbs) against CD4.B molecules, one that recognizes only CD4.B (b1D7) and the other that recognizes both the CD4.A and CD4.B alleles (x1E10) and that can be used to distinguish CD4 T cell subsets by flow cytometry and immunohistochemistry. Using these two mAbs, we identified CD4.A and CD4.B allele-specific proteins on the surface of CD4.A (+/+) and CD4.B (+/+) T cells at a similar level of expression. Moreover, stimulation of peripheral blood mononuclear cells (PBMCs) derived from CD4.A (+/+) and CD4.B (+/+) swine with toxic shock syndrome toxin-1 (TSST-1) in vitro similarly activated both groups of cells that exhibited a slight increase in the CD4/CD8 double positive (DP) cell ratio. A large portion of the DP cells from the allelic CD4.A (+/+) and CD4.B (+/+) groups enhanced the total CD4 and class I swine leukocyte antigen (SLA) expression. The x1E10 mAb delayed and reduced the TSST-1-induced activation of CD4 T cells. Thus, CD4.B appears to be a functional protein whose expression on activated T cells is analogous to CD4.A.


Sujet(s)
Anticorps monoclonaux/immunologie , Antigènes CD4/immunologie , Porc miniature/immunologie , Séquence d'acides aminés , Animaux , Spécificité des anticorps , Antigènes CD4/analyse , Antigènes CD4/composition chimique , Antigènes CD8/analyse , Lignée cellulaire tumorale , Femelle , Génotype , Cellules HEK293 , Antigènes d'histocompatibilité de classe I/génétique , Antigènes d'histocompatibilité de classe I/immunologie , Humains , Agranulocytes/immunologie , Activation des lymphocytes , Mâle , Souris , Souris de lignée BALB C , Modèles moléculaires , Conformation des protéines , Alignement de séquences , Similitude de séquences d'acides aminés , Organismes exempts d'organismes pathogènes spécifiques , Suidae , Porc miniature/génétique , Transfection
17.
Eur J Cancer ; 136: 7-15, 2020 09.
Article de Anglais | MEDLINE | ID: mdl-32622323

RÉSUMÉ

BACKGROUND: Tumour infiltrating lymphocytes (TILs) are an established prognostic biomarker for triple-negative breast cancer (TNBC). We evaluated the role of programmed cell-death ligand-1 (PD-L1), CD8 and FOXP3 expression in refining a prognostic model for non-metastatic TNBC beyond classic factors and TILs. METHODS: Primary tumour samples from 244 early patients with TNBC, all treated with surgery and chemotherapy, were collected. Stromal TILs were evaluated on haematoxylin-eosin slides according to guidelines. PD-L1, CD8 and FOXP3 were assessed by immunohistochemistry and evaluated by digital pathology. RESULTS: TILs, PD-L1, CD8 and FOXP3 were positively correlated with each other (P < 0.001). TILs were confirmed as an independent prognostic factor. When PD-L1, CD8 and FOXP3 were added to multivariable models including classic factors (age, stage, histologic grade) and TILs, PD-L1 provided the largest amount of additional prognostic information: likelihood ratio χ2 4.60, P = 0.032 (in a model including classic factors and TILs 10% increments) and likelihood ratio χ2 6.50, P = 0.011 (in a model including classic factors and TILs >30% versus <30%). In the subset of patients treated with neoadjuvant chemotherapy, FOXP3 provided further prognostic information beyond classic factors, TILs and pathological complete response (pCR) (likelihood ratio χ2 5.01, P = 0.025). For patients who did not achieve a pCR, the expression of CD8 and PD-L1 was significantly increased from baseline to residual disease. CONCLUSIONS: Beyond clinicopathological factors and TILs, other immune biomarkers may add prognostic information for early TNBC. The increased PD-L1 expression on residual disease after neoadjuvant chemotherapy strengthens the rationale of testing immune checkpoint inhibitors in the post-neoadjuvant setting.


Sujet(s)
Antigène CD274/métabolisme , Lymphocytes T CD8+/métabolisme , Facteurs de transcription Forkhead/métabolisme , Lymphocytes TIL/métabolisme , Tumeurs du sein triple-négatives/diagnostic , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Marqueurs biologiques tumoraux/immunologie , Marqueurs biologiques tumoraux/métabolisme , Antigènes CD8/analyse , Antigènes CD8/métabolisme , Lymphocytes T CD8+/immunologie , Lymphocytes T CD8+/anatomopathologie , Études de cohortes , Femelle , Facteurs de transcription Forkhead/analyse , Humains , Immunohistochimie/méthodes , Lymphocytes TIL/immunologie , Lymphocytes TIL/anatomopathologie , Adulte d'âge moyen , Traitement néoadjuvant , Stadification tumorale , Maladie résiduelle , Valeur prédictive des tests , Pronostic , Appréciation des risques/méthodes , Facteurs de risque , Norme de soins , Résultat thérapeutique , Tumeurs du sein triple-négatives/métabolisme , Tumeurs du sein triple-négatives/anatomopathologie , Tumeurs du sein triple-négatives/thérapie
18.
Br J Cancer ; 123(8): 1280-1288, 2020 10.
Article de Anglais | MEDLINE | ID: mdl-32684627

RÉSUMÉ

BACKGROUND: Immunohistochemical quantification of the immune response is prognostic for colorectal cancer (CRC). Here, we evaluate the suitability of alternative immune classifiers on prognosis and assess whether they relate to biological features amenable to targeted therapy. METHODS: Overall survival by immune (CD3, CD4, CD8, CD20 and FOXP3) and immune-checkpoint (ICOS, IDO-1 and PD-L1) biomarkers in independent CRC cohorts was evaluated. Matched mutational and transcriptomic data were interrogated to identify associated biology. RESULTS: Determination of immune-cold tumours by combined low-density cell counts of CD3, CD4 and CD8 immunohistochemistry constituted the best prognosticator across stage II-IV CRC, particularly in patients with stage IV disease (HR 1.98 [95% CI: 1.47-2.67]). These immune-cold CRCs were associated with tumour hypoxia, confirmed using CAIX immunohistochemistry (P = 0.0009), which may mediate disease progression through common biology (KRAS mutations, CRIS-B subtype and SPP1 mRNA overexpression). CONCLUSIONS: Given the significantly poorer survival of immune-cold CRC patients, these data illustrate that assessment of CD4-expressing cells complements low CD3 and CD8 immunohistochemical quantification in the tumour bulk, potentially facilitating immunophenotyping of patient biopsies to predict prognosis. In addition, we found immune-cold CRCs to associate with a difficult-to-treat, poor prognosis hypoxia signature, indicating that these patients may benefit from hypoxia-targeting clinical trials.


Sujet(s)
Tumeurs colorectales/mortalité , Hypoxie tumorale/physiologie , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Antigènes CD3/analyse , Antigènes CD4/analyse , Antigènes CD8/analyse , Tumeurs colorectales/immunologie , Femelle , Humains , Immunohistochimie , Mâle , Adulte d'âge moyen , Pronostic
19.
J Hepatol ; 73(6): 1460-1469, 2020 12.
Article de Anglais | MEDLINE | ID: mdl-32710922

RÉSUMÉ

BACKGROUND & AIMS: Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, led to durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). In our retrospective analysis, we studied the immunobiology and potential associations between biomarkers and outcomes with nivolumab in HCC. METHODS: Fresh and archival tumour samples from dose-escalation and dose-expansion phases of the CheckMate 040 trial were analysed by immunohistochemistry and RNA sequencing to assess several inflammatory gene expression signatures, including CD274 (PD-ligand 1 [PD-L1]), CD8A, LAG3, and STAT1. Biomarkers were assessed for association with clinical outcomes (best overall response by blinded independent central review per RECIST v1.1 and overall survival [OS]). RESULTS: Complete or partial tumour responses were observed in PD-L1-positive and PD-L1-negative patients treated with nivolumab monotherapy. Median OS was 28.1 (95% CI 18.2-n.a.) vs. 16.6 months (95% CI 14.2-20.2) for patients with tumour PD-L1 ≥1% vs. <1% (p = 0.03). Increased CD3 and CD8 showed a non-significant trend towards improved OS (both p = 0.08), and macrophage markers were not associated with OS. Tumour PD-1 and PD-L1 expression were associated with improved OS (p = 0.05 and p = 0.03, respectively). An inflammatory gene signature consisting of 4 genes was associated with improved objective response rate (p = 0.05) and OS (p = 0.01). CONCLUSIONS: PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signatures trended with improved survival and response. While further confirmation within a larger phase III trial is needed to evaluate predictive value of these biomarkers, these exploratory analyses suggest that anti-tumour immune response may play a role in the treatment benefit of nivolumab in HCC. LAY SUMMARY: Certain tests may be used to provide a picture of how a tumour is escaping the immune system, allowing it to continue to grow and create more tumours. Therapies such as nivolumab are designed to help the immune system fight the tumour. These tests may be used to determine how effective such therapies will be in the treatment of advanced liver cancer. NCT NUMBER: NCT01658878.


Sujet(s)
Biomarqueurs pharmacologiques/analyse , Carcinome hépatocellulaire , Tumeurs du foie , Nivolumab , Récepteur-1 de mort cellulaire programmée/antagonistes et inhibiteurs , Antigènes CD/analyse , Antigène CD274/analyse , Marqueurs biologiques tumoraux/analyse , Antigènes CD8/analyse , Carcinome hépatocellulaire/traitement médicamenteux , Carcinome hépatocellulaire/immunologie , Carcinome hépatocellulaire/mortalité , Carcinome hépatocellulaire/anatomopathologie , Surveillance des médicaments/méthodes , Femelle , Humains , Inhibiteurs de points de contrôle immunitaires/administration et posologie , Inhibiteurs de points de contrôle immunitaires/effets indésirables , Immunohistochimie , Ipilimumab/administration et posologie , Ipilimumab/effets indésirables , Tumeurs du foie/traitement médicamenteux , Tumeurs du foie/immunologie , Tumeurs du foie/mortalité , Tumeurs du foie/anatomopathologie , Mâle , Adulte d'âge moyen , Nivolumab/administration et posologie , Nivolumab/effets indésirables , Facteur de transcription STAT-1/analyse , Analyse de survie , Protéine LAG-3
20.
J Pathol Clin Res ; 6(4): 273-282, 2020 10.
Article de Anglais | MEDLINE | ID: mdl-32592447

RÉSUMÉ

The biological complexity reflected in histology images requires advanced approaches for unbiased prognostication. Machine learning and particularly deep learning methods are increasingly applied in the field of digital pathology. In this study, we propose new ways to predict risk for cancer-specific death from digital images of immunohistochemically (IHC) stained tissue microarrays (TMAs). Specifically, we evaluated a cohort of 248 gastric cancer patients using convolutional neural networks (CNNs) in an end-to-end weakly supervised scheme independent of subjective pathologist input. To account for the time-to-event characteristic of the outcome data, we developed new survival models to guide the network training. In addition to the standard H&E staining, we investigated the prognostic value of a panel of immune cell markers (CD8, CD20, CD68) and a proliferation marker (Ki67). Our CNN-derived risk scores provided additional prognostic value when compared to the gold standard prognostic tool TNM stage. The CNN-derived risk scores were also shown to be superior when systematically compared to cell density measurements or a CNN score derived from binary 5-year survival classification, which ignores time-to-event. To better understand the underlying biological mechanisms, we qualitatively investigated risk heat maps for each marker which visualised the network output. We identified patterns of biological interest that were related to low risk of cancer-specific death such as the presence of B-cell predominated clusters and Ki67 positive sub-regions and showed that the corresponding risk scores had prognostic value in multivariate Cox regression analyses (Ki67&CD20 risks: hazard ratio (HR) = 1.47, 95% confidence interval (CI) = 1.15-1.89, p = 0.002; CD20&CD68 risks: HR = 1.33, 95% CI = 1.07-1.67, p = 0.009). Our study demonstrates the potential additional value that deep learning in combination with a panel of IHC markers can bring to the field of precision oncology.


Sujet(s)
Marqueurs biologiques tumoraux/analyse , Apprentissage profond , Interprétation d'images assistée par ordinateur , Immunohistochimie , Tumeurs de l'estomac/composition chimique , Microenvironnement tumoral , Antigènes CD/analyse , Antigènes CD20/analyse , Antigènes de différenciation des myélomonocytes/analyse , Antigènes CD8/analyse , Prolifération cellulaire , Humains , Antigène KI-67/analyse , Stadification tumorale , Valeur prédictive des tests , Appréciation des risques , Facteurs de risque , Tumeurs de l'estomac/mortalité , Tumeurs de l'estomac/anatomopathologie , Facteurs temps , Analyse sur puce à tissus
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