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1.
J Clin Oncol ; 42(1): 70-80, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37788410

RESUMO

PURPOSE: No biomarker capable of improving selection and monitoring of patients with rectal cancer managed by watch-and-wait (W&W) strategy is currently available. Prognostic performance of the Immunoscore biopsy (ISB) was recently suggested in a preliminary study. METHODS: This international validation study included 249 patients with clinical complete response (cCR) managed by W&W strategy. Intratumoral CD3+ and CD8+ T cells were quantified on pretreatment rectal biopsies by digital pathology and converted to ISB. The primary end point was time to recurrence (TTR; the time from the end of neoadjuvant treatment to the date of local regrowth or distant metastasis). Associations between ISB and outcomes were analyzed by stratified Cox regression adjusted for confounders. Immune status of tumor-draining lymph nodes (n = 161) of 17 additional patients treated by neoadjuvant chemoradiotherapy and surgery was investigated by 3'RNA-Seq and immunofluorescence. RESULTS: Recurrence-free rates at 5 years were 91.3% (82.4%-100.0%), 62.5% (53.2%-73.3%), and 53.1% (42.4%-66.5%) with ISB High, ISB Intermediate, and ISB Low, respectively (hazard ratio [HR; Low v High], 6.51; 95% CI, 1.99 to 21.28; log-rank P = .0004). ISB was also significantly associated with disease-free survival (log-rank P = .0002), and predicted both local regrowth and distant metastasis. In multivariate analysis, ISB was independent of patient age, sex, tumor location, cT stage (T, primary tumor; c, clinical), cN stage (N, regional lymph node; c, clinical), and was the strongest predictor for TTR (HR [ISB High v Low], 6.93; 95% CI, 2.08 to 23.15; P = .0017). The addition of ISB to a clinical-based model significantly improved the prediction of recurrence. Finally, B-cell proliferation and memory in draining lymph nodes was evidenced in the draining lymph nodes of patients with cCR. CONCLUSION: The ISB is validated as a biomarker to predict both local regrowth and distant metastasis, with a gradual scaling of the risk of pejorative outcome.


Assuntos
Neoplasias Retais , Conduta Expectante , Humanos , Neoplasias Retais/patologia , Intervalo Livre de Doença , Prognóstico , Quimiorradioterapia , Biópsia , Terapia Neoadjuvante , Recidiva Local de Neoplasia/tratamento farmacológico , Resultado do Tratamento
2.
Cancers (Basel) ; 15(16)2023 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-37627073

RESUMO

BACKGROUND: The Immunoscore (IS) is a quantitative digital pathology assay that evaluates the immune response in cancer patients. This study reports on the reproducibility of pathologists' visual assessment of CD3+- and CD8+-stained colon tumors, compared to IS quantification. METHODS: An international group of expert pathologists evaluated 540 images from 270 randomly selected colon cancer (CC) cases. Concordance between pathologists' T-score, corresponding hematoxylin-eosin (H&E) slides, and the digital IS was evaluated for two- and three-category IS. RESULTS: Non-concordant T-scores were reported in more than 92% of cases. Disagreement between semi-quantitative visual assessment of T-score and the reference IS was observed in 91% and 96% of cases before and after training, respectively. Statistical analyses showed that the concordance index between pathologists and the digital IS was weak in two- and three-category IS, respectively. After training, 42% of cases had a change in T-score, but no improvement was observed with a Kappa of 0.465 and 0.374. For the 20% of patients around the cut points, no concordance was observed between pathologists and digital pathology analysis in both two- and three-category IS, before or after training (all Kappa < 0.12). CONCLUSIONS: The standardized IS assay outperformed expert pathologists' T-score evaluation in the clinical setting. This study demonstrates that digital pathology, in particular digital IS, represents a novel generation of immune pathology tools for reproducible and quantitative assessment of tumor-infiltrated immune cell subtypes.

3.
Oncotarget ; 13: 18-31, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35018217

RESUMO

Because of the function and anatomical environment of the rectum, therapeutic strategies for local advanced rectal cancer (LARC) must deal with two challenging stressors that are a high-risk of local and distal recurrences and a high-risk of poor quality of life (QoL). Over the last three decades, advances in screening tests, therapies, and combined-modality treatment options and strategies have improved the prognosis of patients with LARC. However, owing to the heterogeneous nature of LARC and genetic status, the patient may not respond to a specific therapy and may be at increased risk of side-effects without the life-prolonging benefit. Indeed, each therapy can cause its own side-effects, which may worsen by a combination of treatments resulting in long-term poor QoL. In LARC, QoL has become even more essential with the increasing incidence of rectal cancer in young individuals. Herein, we analyzed the value of the Immunoscore-Biopsy (performed on tumor biopsy at diagnosis) in predicting outcomes, alone or in association with clinical and imaging data, for each therapy used in LARC.


Assuntos
Qualidade de Vida , Neoplasias Retais , Quimiorradioterapia/métodos , Humanos , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/patologia , Prognóstico , Neoplasias Retais/patologia , Reto/patologia , Resultado do Tratamento
4.
Cancers (Basel) ; 13(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805758

RESUMO

Four decades were needed to progress from the first demonstration of the independent prognostic value of lymphocytes infiltration in rectal cancers to the first recommendation from the international guidelines for the use of a standardized immune assay, namely the "Immunoscore" (IS), to accurately prognosticate colon cancers beyond the TNM-system. The standardization process included not only the IS conceptualization, development, fine-tuning, and validation by a large international consortium, but also a demonstration of the robustness and reproducibility across the world and testing of international norms and their effects on the IS. This is the first step of a major change of paradigm that now perceives cancer as the result of contradicting driving forces, i.e., the tumor expansion and the immune response, interacting dynamically and influencing the prognosis and the response to therapies. This prompted us to evaluate and evidence the capacity of the tumor immune status, as reflected by the IS, to accurately predict chemotherapy responses in an international, randomized cohort study of colon cancer. Moreover, we developed a derived IS performed on initial diagnostic biopsies (ISB) to assess response levels to neoadjuvant therapies. In rectal cancer, ISB was positively correlated with the degree of histologic response to neoadjuvant chemoradiotherapy and identified - alone and even more accurately if combined with clinical data- patients eligible for a noninvasive strategy. Based on these results, we are currently setting up an international cohort for confirmation. The potential role of IS with immunotherapies must be anticipated.

5.
J Pathol Clin Res ; 7(1): 27-41, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32902189

RESUMO

Surgical resection of colorectal liver metastases combined with systemic treatment aims to maximize patient survival. However, recurrence rates are very high postsurgery. In order to assess patient prognosis after metastasis resection, we evaluated the main patho-molecular and immune parameters of all surgical specimens. Two hundred twenty-one patients who underwent, after different preoperative treatment, curative resection of 582 metastases were analyzed. Clinicopathological parameters, RAS tumor mutation, and the consensus Immunoscore (I) were assessed for all patients. Overall survival (OS) and time to relapse (TTR) were estimated using the Kaplan-Meier method and compared by log-rank tests. Cox proportional hazard models were used for uni- and multivariate analysis. Immunoscore and clinicopathological parameters (number of metastases, surgical margin, histopathological growth pattern, and steatohepatitis) were associated with relapse in multivariate analysis. Overall, pathological score (PS) that combines relevant clinicopathological factors for relapse, and I, were prognostic for TTR (2-year TTR rate PS 0-1: 49.8.% (95% CI: 42.2-58.8) versus PS 2-4: 20.9% (95% CI: 13.4-32.8), hazard ratio (HR) = 2.54 (95% CI: 1.82-3.53), p < 0.0000; and 2-year TTR rate I 0: 25.7% (95% CI: 16.3-40.5) versus I 3-4: 60% (95% CI: 47.2-76.3), HR = 2.87 (95% CI: 1.73-4.75), p = 0.0000). Immunoscore was also prognostic for OS (HR [I 3-4 versus I 0] = 4.25, 95% CI: 1.95-9.23; p = 0.0001). Immunoscore (HR [I 3-4 versus I 0] = 0.27, 95% CI: 0.12-0.58; p = 0.0009) and RAS mutation (HR [mutated versus WT] = 1.66, 95% CI: 1.06-2.58; p = 0.0265) were significant for OS. In conclusion, PS including relevant clinicopathological parameters and Immunoscore permit stratification of stage IV colorectal cancer patient prognosis in terms of TTR and identify patients with higher risk of recurrence. Immunoscore remains the major prognostic factor for OS.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/patologia , Técnicas de Apoio para a Decisão , Genes ras , Neoplasias Hepáticas/diagnóstico , Mutação , Microambiente Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Hepatectomia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Masculino , Metastasectomia , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Resultado do Tratamento
6.
Clin Cancer Res ; 26(19): 5198-5207, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32669377

RESUMO

PURPOSE: No biomarker to personalize treatment in locally advanced rectal cancer (LARC) is currently available. We assessed in LARC whether a diagnostic biopsy-adapted immunoscore (ISB) could predict response to neoadjuvant treatment (nT) and better define patients eligible to an organ preservation strategy ("Watch-and-Wait"). EXPERIMENTAL DESIGN: Biopsies from two independent cohorts (n 1 = 131, n 2 = 118) of patients with LARC treated with nT followed by radical surgery were immunostained for CD3+ and CD8+ T cells and quantified by digital pathology to determine ISB. The expression of immune-related genes post-nT was investigated (n = 64 patients). Results were correlated with response to nT and disease-free survival (DFS). The ISB prognostic performance was further assessed in a multicentric cohort (n = 73 patients) treated by Watch-and-Wait. RESULTS: ISB positively correlated with the degree of histologic response (P < 0.001) and gene expression levels for Th1 orientation and cytotoxic immune response, post-nT (P = 0.006). ISB high identified patients at lower risk of relapse or death compared with ISB low [HR, 0.21; 95% confidence interval (CI), 0.06-0.78; P = 0.009]. Prognostic performance of ISB for DFS was confirmed in a validation cohort. ISB was an independent parameter, more informative than pre- (P < 0.001) and post-nT (P < 0.05) imaging to predict DFS. ISB combined with imaging post-nT discriminated very good responders that could benefit from organ preservation strategy. In the "Watch-and-Wait" cohort (n = 73), no relapse was observed in patients with ISB high (23.3%). CONCLUSIONS: ISB predicts response to nT and survival in patients with LARC treated by surgery. Its usefulness in the selection of patients eligible for a Watch-and-Wait strategy is strongly suggested.


Assuntos
Biópsia , Complexo CD3/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias Retais/tratamento farmacológico , Idoso , Linhagem da Célula/imunologia , Proliferação de Células/efeitos dos fármacos , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Imunidade/efeitos dos fármacos , Imunidade/imunologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/cirurgia , Seleção de Pacientes , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/imunologia , Neoplasias Retais/cirurgia
7.
Microorganisms ; 8(2)2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31991822

RESUMO

BACKGROUND: The understanding of the pathogenesis of cytomegalovirus (CMV)-induced fetal brain lesions is limited. We aimed to quantify adaptive and innate immune cells and CMV-infected cells in fetal brains with various degrees of brain damage. METHODS: In total, 26 archived embedded fetal brains were studied, of which 21 were CMV-infected and classified in severely affected (n = 13) and moderately affected (n = 8), and 5 were uninfected controls. The respective magnitude of infected cells, immune cells (CD8+, B cells, plasma cells, NK cells, and macrophages), and expression of immune checkpoint receptors (PD-1/PD-L1 and LAG-3) were measured by immunochemistry and quantified by quantitative imaging analysis. RESULTS: Quantities of CD8+, plasma cells, NK cells, macrophages, and HCMV+ cells and expression of PD-1/PD-L1 and LAG-3 were significantly higher in severely affected than in moderately affected brains (all p values < 0.05). A strong link between higher number of stained cells for HCMV/CD8 and PD-1 and severity of brain lesions was found by component analysis. CONCLUSIONS: The higher expression of CD8, PD-1, and LAG-3 in severely affected brains could reflect immune exhaustion of cerebral T cells. These exhausted T cells could be ineffective in controlling viral multiplication itself, leading to more severe brain lesions. The study of the functionality of brain leucocytes ex vivo is needed to confirm this hypothesis.

8.
Chirurgia (Bucur) ; 114(2): 152-161, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31060646

RESUMO

In the fine balance between tumor invasion and our defensive systems, the role played by the adaptive immune response at the tumor site is critical. Beyond the fact that all the immune components of the innate and adaptive response can be observed to varying degrees in the tumor microenvironment, it appears that a high density of T cytotoxic and memory lymphocytes, in a context of Th1 immune orientation in the tumor and its invasion front, provides a prognostic marker of paramount importance for colorectal cancer and more generally all solid tumors. The understanding of the role of immunity in cancer, tailored during one century of intensive research, has led to a complete paradigm shift.based on a sharp dissection In order to show the major impact of this conceptual revolution, we herein retrace through the example of colorectal cancer, how an effective immune test, namely the "Immunoscore", has been developed. We also provide up to date data demonstrating the capacity of the Immunoscore to prognosticate with a better accuracy than the TME classification clinical outcomes and to guide therapeutic strategies.


Assuntos
Neoplasias do Colo/imunologia , Indicadores Básicos de Saúde , Neoplasias Retais/imunologia , Microambiente Tumoral/imunologia , Imunidade Adaptativa/imunologia , Humanos , Prognóstico , Células Th1/imunologia , Resultado do Tratamento
9.
Cancer Cell ; 34(6): 1012-1026.e3, 2018 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-30537506

RESUMO

Treatment of metastatic colorectal cancer is based upon the assumption that metastases are homogeneous within a patient. We quantified immune cell types of 603 whole-slide metastases and primary colorectal tumors from 222 patients. Primary lesions, and synchronous and metachronous metastases, had a heterogeneous immune infiltrate and mutational diversity. Small metastases had frequently a low Immunoscore and T and B cell score, while a high Immunoscore was associated with a lower number of metastases. Anti-epidermal growth factor receptor treatment modified immune gene expression and significantly increased T cell densities in the metastasis core. The predictive accuracy of the Immunoscore from a single biopsy was superior to the one of programmed cell death ligand 1 (PD-L1). The immune phenotype of the least-infiltrated metastasis had a stronger association with patient outcome than other metastases.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Estudos de Coortes , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Receptores ErbB/imunologia , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
10.
J Natl Cancer Inst ; 110(1)2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28922789

RESUMO

Background: This study assesses how the metastatic immune landscape is impacting the response to treatment and the outcome of colorectal cancer (CRC) patients. Methods: Complete curative resection of metastases (n = 441) was performed for two patient cohorts (n = 153). Immune densities were quantified in the center and invasive margin of all metastases. Immunoscore and T and B cell (TB) score were analyzed in relation to radiological and pathological responses and patient's disease-free (DFS) and overall survival (OS) using multivariable Cox proportional hazards models. All statistical tests were two-sided. Results: The spatial distribution of immune cells within metastases was nonuniform. Patients, as well as metastases of the same patient, had variable immune infiltrates and response to therapy. A beneficial response was statistically significantly associated with increased immune densities. Among all metastases, Immunoscore (I) and TB score evaluated in the least immune-infiltrated metastases were the strongest predictors for DFS and OS (five-year follow-up, Immunoscore: I 3-4: DFS rate = 27.9%, 95% CI = 15.2 to 51.3; vs I 0-1-2: DFS rate = 12.3%, 95% CI = 4.9 to 30.6; HR = 0.45, 95% CI = 0.28 to 0.70, P = .02; I 3-4: OS rate = 64.6%, 95% CI = 46.6 to 89.6; vs I 0-1-2: OS rate = 32.5%, 95% CI = 17.2 to 61.4; HR = 0.32, 95% CI = 0.15 to 0.66, P = .001, C-index = 65.9%; five-year follow-up, TB score: TB 3-4: DFS rate = 25.7%, 95% CI = 14.2 to 46.6; vs TB 0-1-2: DFS rate = 5.0%, 95% CI = 0.8 to 32.4; HR = 0.36, 95% CI = 0.22 to 0.57, P < .001; TB 3-4: OS rate = 63.7%, 95% CI = 46.4 to 87.5; vs TB 0-1-2: OS rate: 21.4%, 95% CI = 9.2 to 49.8; HR = 0.25, 95% CI = 0.12 to 0.51, P < .001, C-index = 67.8%). High TB score and Immunoscore patients had a median survival of 70.5 months, while low patients survived only 25.1 to 38.3 months. Nonresponding patients with high-immune infiltrates had prolonged DFS (HR = 0.28, 95% CI = 0.15 to 0.52, P = .001) and OS (HR = 0.25, 95% CI = 0.1 to 0.62, P = .001). The immune parameters remained the only statistically significant prognostic factor associated with DFS and OS in multivariable analysis (P < .001), while response to treatment was not. Conclusions: Response to treatment and prolonged survival of metastatic CRC patients were statistically significantly associated with high-immune densities quantified into the least immune-infiltrated metastasis.


Assuntos
Linfócitos B , Neoplasias Colorretais/imunologia , Neoplasias Hepáticas/imunologia , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral , Linfócitos T , Idoso , Antígenos CD20/análise , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/química , Complexo CD3/análise , Linfócitos T CD8-Positivos , Quimioterapia Adjuvante , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Intervalo Livre de Doença , Seguimentos , Fatores de Transcrição Forkhead/análise , Hepatectomia , Humanos , Antígenos Comuns de Leucócito/análise , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Contagem de Linfócitos , Metastasectomia , Pessoa de Meia-Idade , Metástase Neoplásica , Pneumonectomia , Período Pré-Operatório , Critérios de Avaliação de Resposta em Tumores Sólidos , Taxa de Sobrevida , Linfócitos T/química , Microambiente Tumoral/imunologia
11.
Ann Pathol ; 37(1): 29-38, 2017 Feb.
Artigo em Francês | MEDLINE | ID: mdl-28161000

RESUMO

The role of the immune response at the tumor site is now recognized as crucial in the clinical course of patients with cancer. The importance of the immune cell type, their functional orientation, their density and location within the tumor's regions (tumor/invasion margin) has recently been shown and were grouped together under the term "immune contexture". A strong infiltration by cytotoxic and memory T cells in a Th1-polarized tumor microenvironment appears to have a major prognosis impact. A test called Immunoscore taking into account these various parameters has been suggested to measure in a simple, reproducible and robust manner the intra- and peritumoral immune response. The prognostic value of Immunoscore has recently been validated in colon cancers by a large international retrospective study under the aegis of the Society for Immunotherapy of Cancer (SITC). The Immunoscore could have several potential clinical applications such as prognostic as well as theranostic.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imuno-Histoquímica/métodos , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/imunologia , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia , Complexo CD3/análise , Antígenos CD8/análise , Progressão da Doença , Humanos , Memória Imunológica , Imunoterapia , Antígenos Comuns de Leucócito/análise , Linfócitos do Interstício Tumoral/química , Invasividade Neoplásica/imunologia , Estadiamento de Neoplasias , Neoplasias/patologia , Neoplasias/terapia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Estudos de Validação como Assunto
12.
Int Immunol ; 28(8): 373-82, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27121213

RESUMO

The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) tumor, nodes, metastasis (TNM) classification system based on tumor features is used for prognosis estimation and treatment recommendations in most cancers. However, the clinical outcome can vary significantly among patients within the same tumor stage and TNM classification does not predict response to therapy. Therefore, many efforts have been focused on the identification of new markers. Multiple tumor cell-based approaches have been proposed but very few have been translated into the clinic. The recent demonstration of the essential role of the immune system in tumor progression has allowed great advances in the understanding of this complex disease and in the design of novel therapies. The analysis of the immune infiltrate by imaging techniques in large patient cohorts highlighted the prognostic impact of the in situ immune cell infiltrate in tumors. Moreover, the characterization of the immune infiltrates (e.g. type, density, distribution within the tumor, phenotype, activation status) in patients treated with checkpoint-blockade strategies could provide information to predict the disease outcome. In colorectal cancer, we have developed a prognostic score ('Immunoscore') that takes into account the distribution of the density of both CD3(+) lymphocytes and CD8(+) cytotoxic T cells in the tumor core and the invasive margin that could outperform TNM staging. Currently, an international retrospective study is under way to validate the Immunoscore prognostic performance in patients with colon cancer. The use of Immunoscore in clinical practice could improve the patients' prognostic assessment and therapeutic management.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Monitorização Imunológica/métodos , Neoplasias/diagnóstico , Linfócitos T Citotóxicos/imunologia , Complexo CD3/metabolismo , Antígenos CD8/metabolismo , Humanos , Ativação Linfocitária , Estadiamento de Neoplasias , Neoplasias/classificação , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Prognóstico
13.
Clin Cancer Res ; 20(7): 1891-9, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24691640

RESUMO

PURPOSE: To determine whether the tumor immune infiltrate, as recently evaluated with the Immunoscore methodology, could be a useful prognostic marker in patients with rectal cancers. EXPERIMENTAL DESIGN: The influence of the immune infiltrate on patient's outcome was investigated in patients with or without preoperative chemoradiation therapy (pCRT). The density of total (CD3(+)) and cytotoxic (CD8(+)) T lymphocytes was evaluated by immunohistochemistry and quantified by a dedicated image analysis software in surgical specimens of patients with rectal cancer (n = 111) who did not receive pCRT and in tumor biopsies performed before pCRT from additional 55 patients. The results were correlated with tumor recurrence, patient's survival, and response to pCRT. RESULTS: The densities of CD3(+) and CD8(+) lymphocytes and the associated Immunoscore (from I0 to I4) were significantly correlated with differences in disease-free and overall survival (HR, 1.81 and 1.72, respectively; all P < 0.005). Cox multivariate analysis supports the advantage of the Immunoscore compared with the tumor-node-metastasis (TNM) staging in predicting recurrence and survival (all P < 0.001). Lymph node ratio added information in a prognostic model (all P < 0.05). In addition, high infiltration of CD3(+) and CD8(+) lymphocytes in tumor biopsies was associated with downstaging of the tumor after pCRT (CD3(+) cells; Fisher exact test P = 0.01). CONCLUSIONS: The Immunoscore could be a useful prognostic marker in patients with rectal cancer treated by primary surgery. The determination of the immune infiltrate in biopsies before treatment could be a valuable information for the prediction of response to pCRT.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/radioterapia , Neoplasias Retais/imunologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , Complexo CD3/imunologia , Terapia Combinada , Feminino , Humanos , Metástase Linfática/imunologia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Dosagem Radioterapêutica , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Neoplasias Retais/radioterapia , Resultado do Tratamento
14.
J Immunother ; 33(9): 991-8, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20948437

RESUMO

Sunitinib, an antiangiogenic molecule, is one of the first-line standard of care in the treatment of patients with metastatic renal cell carcinoma. However, it only benefits to a subgroup of patients and no predictive markers of sunitinib efficacy have been identified. Twenty-eight metastatic renal cell carcinomas were treated with sunitinib-based therapy and another subgroup of 7 primary renal cell cancer patients were also treated by sunitinib in a neoadjuvant trial. Measurements of CD3+CD4+CD25(hi) Foxp3+ regulatory T cells, an immunosuppressive cell population, were performed before and after each cycle of treatment in blood and tumor in a prospective study. We observed a decrease in the number of peripheral blood Foxp3+ regulatory T cells after each cycle of sunitinib-based therapy. The overall survival was significantly longer in patients showing a decrease in the number of Foxp3+ regulatory T cells after 2 or 3 cycles of treatment (P<0.05). The decrease in the number of regulatory T cells positively correlated with their number at baseline (P<0.01), but not with modification of tumor volume defined by Response Evaluation Criteria in Solid Tumors criteria. The clinical relevance of these results was also supported by an intratumoral decrease of regulatory T cells in 5 out of 7 patients treated by sunitinib in a neoadjuvant trial. Our study represents the first work reporting that the measurement of regulatory T cells may have a predictive value on antiangiogenic response. Antiangiogenic therapy also reversed immunosuppression in the tumor microenvironment which provides novel argument in human to favor its combination with immunotherapy.


Assuntos
Adenocarcinoma de Células Claras/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Renais/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Adenocarcinoma de Células Claras/imunologia , Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma de Células Claras/fisiopatologia , Adenocarcinoma de Células Claras/secundário , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Bevacizumab , Contagem de Células , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Fatores de Transcrição Forkhead/biossíntese , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Neoplasias Renais/imunologia , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Neoplasias Renais/fisiopatologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/fisiopatologia , Neoplasias Pulmonares/secundário , Masculino , Terapia Neoadjuvante , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Sunitinibe , Análise de Sobrevida , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia
15.
FEBS Lett ; 582(2): 185-9, 2008 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-18070601

RESUMO

The homopentameric B-subunit of Shiga toxin (STxB) is used as a tool to deliver antigenic peptides and proteins to the cytosolic compartment of dendritic cells (DCs). In this study, a series of interface mutants of STxB has been constructed. All mutants retained their overall conformation, while a loss in thermal stability was observed. This effect was even more pronounced in trifluoroethanol solutions that mimic the membrane environment. Despite this, all mutants were equally efficient at delivering a model antigenic protein into the MHC class I-restricted antigen presentation pathway of mouse DCs, suggesting that the structural stability of STxB is not a key factor in the membrane translocation process.


Assuntos
Antígenos/imunologia , Mutação , Toxinas Shiga/química , Dicroísmo Circular , Imunofluorescência , Células HeLa , Humanos , Modelos Moleculares , Conformação Proteica , Toxinas Shiga/genética , Toxinas Shiga/imunologia , Espectrofotometria Ultravioleta
16.
J Immunother ; 31(1): 101-12, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18157017

RESUMO

The primary goal of cancer vaccines is to induce CD8+ T cells specific for tumor-associated antigens (TAA) but the characterization of these cells has been difficult because of the low sensitivity of ex vivo assays. Here, we focused on TAA-specific CD8+ T-cell responses in melanoma patients after vaccination with autologous dendritic cells loaded with lysates derived from allogeneic tumor-cell lines (Lysate-DC). Out of 40 patients treated, 16 patients developed immune response to tumor-cell lysate and/or CD8+ T cells specific for differentiation and cancer-testis antigens. TAA-specific CD8+ T-cell responses were detected by interferon (IFN)-gamma enzyme-linked immunospot after in vitro sensitization and were, either transient during the treatment period or delayed, that is, observed after completion of all vaccinations. We could not correlate these immune responses to clinical data as none of the patients achieved an overall objective response according to Response Evaluation Criteria in Solid Tumors criteria. Three patients were reported as stable disease and 10 patients presented evidence of antitumor activity. We found that TAA-specific T cells characterized in 4 patients produced perforin ex vivo, but no IFN-gamma in enzyme-linked immunospot. Differential expression of IFN-gamma and perforin was also observed for viral-specific T cells. Altogether, our results show that Lysate-DC therapy elicited tumor-specific CD8+ T cells nonlimited to human leukocyte antigen-A2+ patients, with some T cells secreting perforin ex vivo and IFN-gamma only after restimulation. The differential expression of perforin and IFN-gamma by antitumor and antiviral CD8+ T cells supports that the sole use of IFN-gamma production to monitor T cells overlooks functional T-cell subpopulations triggered by vaccines.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/uso terapêutico , Células Dendríticas/transplante , Melanoma/terapia , Linfócitos T/imunologia , Antígenos Virais/imunologia , Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Epitopos de Linfócito T/imunologia , Humanos , Interferon gama/metabolismo , Cinética , Leucócitos Mononucleares/imunologia , Ativação Linfocitária/imunologia , Melanoma/imunologia , Melanoma/patologia , Metástase Neoplásica , Perforina/metabolismo , Linfócitos T/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Resultado do Tratamento
17.
J Immunol ; 179(5): 3371-9, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17709554

RESUMO

The nontoxic B subunit of Shiga toxin (STxB) targets in vivo Ag to dendritic cells that preferentially express the glycolipid Gb(3) receptor. After administration of STxB chemically coupled to OVA (STxB-OVA) or E7, a polypeptide derived from HPV, in mice, we showed that the addition of alpha-galactosylceramide (alpha-GalCer) resulted in a dramatic improvement of the STxB Ag delivery system, as reflected by the more powerful and longer lasting CD8(+) T cell response observed even at very low dose of immunogen (50 ng). This synergy was not found with other adjuvants (CpG, poly(I:C), IFN-alpha) also known to promote dendritic cell maturation. With respect to the possible mechanism explaining this synergy, mice immunized with alpha-GalCer presented in vivo the OVA(257-264)/K(b) complex more significantly and for longer period than mice vaccinated with STxB alone or mixed with other adjuvants. To test whether this vaccine could break tolerance against self Ag, OVA transgenic mice were immunized with STxB-OVA alone or mixed with alpha-GalCer. Although no CTL induction was observed after immunization of OVA transgenic mice with STxB-OVA, tetramer assay clearly detected specific anti-OVA CD8(+) T cells in 8 of 11 mice immunized with STxB-OVA combined with alpha-GalCer. In addition, vaccination with STxB-OVA and alpha-GalCer conferred strong protection against a challenge with vaccinia virus encoding OVA with virus titers in the ovaries reduced by 5 log compared with nonimmunized mice. STxB combined with alpha-GalCer therefore appears as a promising vaccine strategy to more successfully establish protective CD8(+) T cell memory against intracellular pathogens and tumors.


Assuntos
Autoantígenos/imunologia , Galactosilceramidas/farmacologia , Tolerância Imunológica/efeitos dos fármacos , Toxinas Shiga/farmacologia , Vacinas Sintéticas/farmacologia , Vacínia/prevenção & controle , Animais , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Sinergismo Farmacológico , Galactosilceramidas/química , Galactosilceramidas/imunologia , Camundongos , Camundongos Transgênicos , Proteínas Oncogênicas Virais/química , Proteínas Oncogênicas Virais/imunologia , Ovalbumina/química , Ovalbumina/genética , Ovalbumina/imunologia , Proteínas E7 de Papillomavirus , Peptídeos/química , Peptídeos/imunologia , Peptídeos/farmacologia , Toxinas Shiga/química , Toxinas Shiga/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Vacinas Sintéticas/química , Vacinas Sintéticas/imunologia , Vaccinia virus/imunologia
18.
Ann Pathol ; 25(3): 211-9, 2005 Jun.
Artigo em Francês | MEDLINE | ID: mdl-16230947

RESUMO

In preclinical tumor model and in human cancer, tumor antigen specific T lymphocytes play a key role in the control of tumor development. Nevertheless in numerous cases, the infiltrating tumor T cells do not seem to influence the clinical progression of the tumor. A better phenotypic and functional characterization of T cells in close contact with tumor associated with a comprehensive analysis of tumor evasion mechanism to the host response should lead to an optimization of cancer immunotherapy protocols.


Assuntos
Neoplasias/imunologia , Neoplasias/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Antígenos CD/imunologia , Humanos , Linfócitos do Interstício Tumoral/patologia , Prognóstico
19.
Bull Cancer ; 90(8-9): 677-85, 2003.
Artigo em Francês | MEDLINE | ID: mdl-14609756

RESUMO

Experiments in mice and recent human clinical studies have clearly shown the contribution of CD8+ T lymphocyte in the control of tumor development. CD8+ T lymphocytes are a constitutive component of the immune response during the development of cancer. In murine models, the efficiency of various cancer vaccines mainly depends on their ability to induce CD8+ T lymphocytes. Clinical responses in immunotherapy treated cancer patients have been associated with the presence of antitumor specific CD8+ T lymphocytes. In spontaneous regressive melanomas, intratumor antigen specific CD8+ cytotoxic T cells were expanded suggesting their involvement in the tumor shrinkage. Administration of antitumor specific cytotoxic T clones in mice resulted in antitumor responses which directly demonstrated the therapeutic efficiency of these cells. However, in most cases during cancer progression, the presence of antitumor CD8 T lymphocyte is not associated with clinical responses. Intrinsic functional abnormalities of these cells or a defect of CD8+ T cell migration to the tumor may in part explain their failure to inhibit tumor development. On the other hand, tumors also develop immune escape mechanisms (down modulation of tumor antigens, secretion of immunosuppressive factors, expression of anti-apoptotic molecules by the tumors, or pro-apoptotic factors inducing T cell death) to resist to the CD8+ T cell attack. To circumvent these tumor escape mechanisms, efficient cancer vaccines will have to recruit CD8+ T cells associated with other immune effectors.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Vigilância Imunológica/fisiologia , Imunoterapia/métodos , Neoplasias/terapia , Animais , Linfócitos T CD8-Positivos/transplante , Vacinas Anticâncer/imunologia , Citotoxicidade Imunológica , Humanos , Imunoterapia Ativa , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Neoplasias/imunologia , Linfócitos T Citotóxicos
20.
Int Immunol ; 15(10): 1161-71, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-13679386

RESUMO

A number of studies in animal models and humans have shown that both humoral andcell-mediated immune responses play an important role in the control of viral infection and tumor development. In most cases, vaccination with non-vectorized peptides or proteins induces low antibody responses and fails to elicit specific cytotoxic T lymphocytes (CTL). In order to make vaccination more efficient, we chemically coupled the non-toxic B subunit of Shiga toxin (STxB) to a full-size antigenic model protein, ovalbumin (OVA), yielding STxB-OVA. We found that STxB-OVA delivers OVA-derived peptides into both the MHC class I- and II-restricted presentation pathways in mouse dendritic cells. Accordingly, the study of STxB trafficking in these cells revealed that, after internalization, a fraction of STxB followed the retrograde transport pathway to the endoplasmic reticulum, while another fraction was targeted to late endosomes/lysosomes. Vaccination of mice with STxB-OVA primed a specific anti-OVA CTL response without the use of adjuvants. Splenocytes and, particularly, CD4(+) T cells from mice immunized with STxB-OVA also produced higher amounts of the T(h)1 cytokine IFN-gamma and IgG2a-type antibodies than mice immunized with non-vectorized ovalbumin. In conclusion, this study identifies a unique non-live vaccine delivery system for polyepitopic antigens that elicits antigen-specific CTL, a humoral immune response and a T(h)1-type polarization without the use of adjuvant.


Assuntos
Formação de Anticorpos , Ovalbumina/imunologia , Toxinas Shiga/genética , Linfócitos T Citotóxicos/imunologia , Células Th1/imunologia , Animais , Antígenos/imunologia , Cisteína Endopeptidases/fisiologia , Feminino , Genes MHC Classe I/genética , Genes MHC da Classe II/genética , Genes MHC da Classe II/imunologia , Camundongos , Complexos Multienzimáticos/fisiologia , Ovalbumina/genética , Ovalbumina/metabolismo , Complexo de Endopeptidases do Proteassoma , Processamento de Proteína Pós-Traducional , Receptores de Superfície Celular/fisiologia , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismo , Toxina Shiga/imunologia , Toxina Shiga/metabolismo , Transdução de Sinais
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