المؤلفون: Victor Sarradin, Amélie Lusque, Thomas Filleron, Florence Dalenc, Camille Franchet

المصدر: Breast Cancer Research, Vol 23, Iss 1, Pp 1-11 (2021)

مصطلحات موضوعية: Triple-negative breast cancer, Neoadjuvant chemotherapy, Immune microenvironment, Tumor-infiltrating lymphocytes, TILs, PD-L1, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background The immune microenvironment (IME) of triple-negative breast cancers (TNBCs) and its modulation by neoadjuvant chemotherapy (NACT) remain to be fully characterized. Our current study aims to evaluate NACT-induced IME changes and assess the prognostic value of specific immune biomarkers. Methods Tumor-infiltrating lymphocytes (TILs) were identified from hematoxylin-eosin-stained sections of paired pre- and post-NACT tumor samples from a TNBC cohort (n = 66) and expression of PD-L1, TIM-3, and LAG-3 evaluated by immunohistochemistry. Results Overall TIL counts and PD-L1 expression did not differ pre- and post-NACT, but there was a response-specific statistically significant difference. TIL counts decreased in 65.5% of patients who achieved a pathological complete response (pCR) and increased in 56.8% of no-pCR patients (p = 0.0092). PD-L1 expression was significantly more frequently lost after NACT in pCR than in no-pCR patients (41.4% vs 16.2%, p = 0.0020). TIM-3 positivity (≥ 1%) was significantly more frequent after NACT (p 10%) was significantly associated with better overall survival (OS), p = 0.0112. After NACT, PD-L1 positivity and strong TIM-3 positivity (≥ 5%) were both associated with significantly worse OS (p = 0.0055 and p = 0.0274, respectively). Patients positive for both PD-L1 and TIM-3 had the worst prognosis (p = 0.0020), even when only considering patients who failed to achieve a pCR, p = 0.0479. Conclusions NACT induces significant IME changes in TNBCs. PD-L1 and TIM-3 expression post-NACT may yield important prognostic information for TNBC patients.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1465-542XTest

الوصول الحر: https://doaj.org/article/1e4648556cd94fd8825881faa3eb2701Test

المؤلفون: Carlos Martinez-Gomez, Marie Michelas, Clara-Maria Scarlata, Anna Salvioni, Carlos Gomez-Roca, Victor Sarradin, Françoise Lauzéral-Vizcaino, Virginie Féliu, Agnès Dupret-Bories, Gwénaël Ferron, Jérôme Sarini, Christel Devaud, Jean-Pierre Delord, Camille-Charlotte Balança, Alejandra Martinez, Maha Ayyoub

المصدر: Cancers, Vol 14, Iss 15, p 3679 (2022)

مصطلحات موضوعية: CD4 T-cell response, tumor antigens, cancer immunotherapy, circulating biomarkers, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Tumor-infiltrating exhausted PD-1hiCD39+ tumor-antigen (Ag)-specific CD4 T cells contribute to the response to immune checkpoint blockade (ICB), but their circulating counterparts, which could represent accessible biomarkers, have not been assessed. Here, we analyzed circulating PD-1+CD39+ CD4 T cells and show that this population was present at higher proportions in cancer patients than in healthy individuals and was enriched in activated HLA-DR+ and ICOS+ and proliferating KI67+ cells, indicative of their involvement in ongoing immune responses. Among memory CD4 T cells, this population contained the lowest proportions of cells producing effector cytokines, suggesting they were exhausted. In patients with HPV-induced malignancies, the PD-1+CD39+ population contained high proportions of HPV Ag-specific T cells. In patients treated by ICB for HPV-induced tumors, the proportion of circulating PD-1+CD39+ CD4 T cells was predictive of the clinical response. Our results identify CD39 expression as a surrogate marker of circulating helper tumor-Ag-specific CD4 T cells.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2072-6694/14/15/3679Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/ba11c9ace1eb4d6d83c4caa3df92a4c9Test

المؤلفون: Camille-Charlotte Balança, Anna Salvioni, Clara-Maria Scarlata, Marie Michelas, Carlos Martinez-Gomez, Carlos Gomez-Roca, Victor Sarradin, Marie Tosolini, Carine Valle, Frédéric Pont, Gwénaël Ferron, Laurence Gladieff, Sébastien Vergez, Agnès Dupret-Bories, Eliane Mery, Philippe Rochaix, Jean-Jacques Fournié, Jean-Pierre Delord, Christel Devaud, Alejandra Martinez, Maha Ayyoub

المصدر: JCI Insight, Vol 6, Iss 2 (2021)

مصطلحات موضوعية: Immunology, Medicine

الوصف: Tumor antigen–specific CD4 T cells accumulate at tumor sites, evoking their involvement in antitumor effector functions in situ. Contrary to CD8 cytotoxic T lymphocyte exhaustion, that of CD4 T cells remains poorly appreciated. Here, using phenotypic, transcriptomic, and functional approaches, we characterized CD4 T cell exhaustion in patients with head and neck, cervical, and ovarian cancer. We identified a CD4 tumor-infiltrating lymphocyte (TIL) population, defined by high PD-1 and CD39 expression, which contained high proportions of cytokine-producing cells, although the quantity of cytokines produced by these cells was low, evoking an exhausted state. Terminal exhaustion of CD4 TILs was instated regardless of TIM-3 expression, suggesting divergence with CD8 T cell exhaustion. scRNA-Seq and further phenotypic analyses uncovered similarities with the CD8 T cell exhaustion program. In particular, PD-1hiCD39+ CD4 TILs expressed the exhaustion transcription factor TOX and the chemokine CXCL13 and were tumor antigen specific. In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently higher tumor-specific CD8 T cell proliferation. Our data identify exhausted CD4 TILs as players in responsiveness to immune checkpoint blockade.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2379-3708Test

الوصول الحر: https://doaj.org/article/8b7de59e26a544eda70bdfbd5f4d8749Test

المؤلفون: Victor, Sarradin, Sarah, Betrian, Léonor, Chaltiel, Clémence, Brac De La Perriere, Jean Pierre, Delord

المصدر: Bulletin du Cancer. 110:168-173

مصطلحات موضوعية: Cancer Research, Oncology, Radiology, Nuclear Medicine and imaging, Hematology, General Medicine

الوصف: Sinonasal intestinal-type adenocarcinoma (ITAC) is a rare tumor, typically found in the ethmoid or upper nasal cavity. There is no standard systemic treatment for metastatic/locally advanced disease ineligible for upfront surgery or radiotherapy.Patients treated between 2015 and 2021 in our institution with a fluoropyrimidine plus oxaliplatin and/or irinotecan for advanced ITAC were retrospectively assessed for overall survival (OS), progression-free survival (PFS) and tumoral responses.Six patients without meningeal involvement received chemotherapy (three FOLFOX, two FOLFIRI, one FOLFIRINOX). All achieved a response, including those with brain extension. Median PFS with FOLFOX and FOLFIRI was similar (6.0 months, 95%CI 5.8-NR; 5.8 months, 95%CI 5.8-NR respectively). Three patients had meningeal involvement with meningitis symptoms and received first-line therapy. All had rapid disease progression (median PFS 1.2 months, 95%CI 1.0-NR) DISCUSSION: FOLFOX, FOLFIRI or FOLFIRINOX appear to have anti-tumor efficacy for metastatic or locally advanced unresectable ITAC, except in cases of carcinomatous meningitis. These regimens require further evaluation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f3da17ece000d904f1598e309e264b9aTest
https://doi.org/10.1016/j.bulcan.2022.10.004Test

المؤلفون: Victor Sarradin (10881394), Amélie Lusque (10331260), Thomas Filleron (2183932), Florence Dalenc (15454), Camille Franchet (6241610)

مصطلحات موضوعية: Medicine, Cell Biology, Molecular Biology, Immunology, Cancer, Infectious Diseases, Plant Biology, Virology, Computational Biology, Space Science, Biological Sciences not elsewhere classified, Triple-negative breast cancer, Neoadjuvant chemotherapy, Immune microenvironment, Tumor-infiltrating lymphocytes, TILs, PD-L1, TIM-3, LAG-3, Immune checkpoint

الوصف: Additional file 1: Table S1. Patients characteristics. Non-ductal histologic subtypes include one metaplastic chondroid (grade 2, no-pCR), one muco-epidermoid (grade 3, no-pCR) and one epidermoid metaplastic (grade 3, pCR). Abbreviations: D= docetaxel 100 mg/m2 (D1=D21), wP= weekly paclitaxel (80 mg/m2), (F)EC = 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), cyclophosphamide (500 mg/m2). Table S2. Description of IME characteristics before and after chemotherapy, as a function of NACT response (pCR and no-pCR groups). Percentages for the pCR and no-pCR groups shown were calculated for each individual row. Table S3. Changes of IME characteristics induced by neoadjuvant chemotherapy, for the entire population, and as a function of the NACT response (pCR and no-pCR groups). Table S4. Overall survival at 3 years according to the initial clinical-pathological characteristics, as a function of core biopsy immune biomarkers (before chemotherapy) and vascular invasion evaluated on the surgical sample (after chemotherapy). Table S5. Association between overall survival (OS) and TILs, TIM-3 and LAG-3 evaluated as continuous variables.

العلاقة: https://figshare.com/articles/journal_contribution/Additional_file_1_of_Immune_microenvironment_changes_induced_by_neoadjuvant_chemotherapy_in_triple-negative_breast_cancers_the_MIMOSA-1_study/14684614Test

الإتاحة: https://doi.org/10.6084/m9.figshare.14684614.v1Test

المؤلفون: Maha Ayyoub, Alejandra Martinez, Philippe Rochaix, Jean-Pierre Delord, Sébastien Vergez, Jean-Jacques Fournié, Eliane Mery, Aurore Siegfried-Vergnon, Claire Illac, Benjamin Vairel, Jérôme Sarini, Agnès Dupret-Bories, Yann Tanguy Le Gac, Stéphanie Motton, Laurence Gladieff, Gwénaël Ferron, Frédéric Pont, Carine Valle, Virginie Féliu, Lucile Mir-Mesnier, Françoise Lauzéral-Vizcaino, Diana Heaugwane, Marie Tosolini, Carlos Gomez-Roca, Carlos Martinez Gomez, Camille Franchet, Victor Sarradin, Christel Devaud, Marie Michelas, Clara-Maria Scarlata, Camille-Charlotte Balança

الوصف: Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in patients with cancer could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggest a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8+ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor–specific CD8+ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors, leading, in situ, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison with their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor–specific CD8+ T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated patients with head and neck cancer. Our results showed that PD-1 blockade–mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::15088e85b65bc7abc71df678f13c4143Test
https://doi.org/10.1158/2326-6066.c.6550446.v1Test

المؤلفون: Maha Ayyoub, Alejandra Martinez, Philippe Rochaix, Jean-Pierre Delord, Sébastien Vergez, Jean-Jacques Fournié, Eliane Mery, Aurore Siegfried-Vergnon, Claire Illac, Benjamin Vairel, Jérôme Sarini, Agnès Dupret-Bories, Yann Tanguy Le Gac, Stéphanie Motton, Laurence Gladieff, Gwénaël Ferron, Frédéric Pont, Carine Valle, Virginie Féliu, Lucile Mir-Mesnier, Françoise Lauzéral-Vizcaino, Diana Heaugwane, Marie Tosolini, Carlos Gomez-Roca, Carlos Martinez Gomez, Camille Franchet, Victor Sarradin, Christel Devaud, Marie Michelas, Clara-Maria Scarlata, Camille-Charlotte Balança

الوصف: Supplementary Figures S1-S10 and Tables S1-S3

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8aa04b91de56803092bd709f5564e145Test
https://doi.org/10.1158/2326-6066.22543884Test

المؤلفون: Victor Sarradin, Mony Ung, Camille Franchet, Vincent Nicolaï, Florence Dalenc

المصدر: Bulletin du Cancer. 108:67-79

مصطلحات موضوعية: 0301 basic medicine, Cancer Research, Antibody-drug conjugate, Mutation, Tumor-infiltrating lymphocytes, business.industry, DNA damage, Hematology, General Medicine, medicine.disease_cause, medicine.disease, Clinical trial, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Breast cancer, Oncology, 030220 oncology & carcinogenesis, Cancer research, Cytotoxic T cell, Medicine, Radiology, Nuclear Medicine and imaging, Receptor, business

الوصف: Compared with other breast cancer subtypes, patients with metastatic triple-negative breast cancer (TNBC) are younger and have a worst overall survival with a median of 15 to 18 months. These tumors have long suffered from a purely negative definition, but the last few years have witnessed many breakthrough genomic and molecular findings, that could dramatically improve our understanding of the biological heterogeneity of TNBC. Moreover, based on these genomic analyses, new generation of clinical trials, using many innovative therapies directed against novel targets, had been conducted. Some TNBC have DNA damage response defects, particularly linked to germinal BRCA1/2 mutations. At the present time, two poly(ADP-ribose) polymerase (PARP) inhibitors have been approved for patients with germinal BRCA1/2 mutation. Breast cancers are not the more immunogenic solid tumors, but some of them have a high percentage of tumor infiltrating lymphocytes (TILs), express PD-L1 (about 40%) or have a high tumor mutational burden. These features of TNBC have given a strong rational to investigate the role of immune checkpoint inhibitors. One of them has been approved by FDA in association with a cytotoxic as a first line treatment. At last, targeting surface receptors outside genomic landscape with antibody drug conjugate (ADC) is a new strategy for metastatic TNBC. Sacituzumab-govitecan is the first ADC approved by FDA in advanced TNBC beyond two lines of treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::f7492391ab7780ac168049f542c3eed0Test
https://doi.org/10.1016/j.bulcan.2020.11.007Test

المؤلفون: Victor Sarradin, Carine Valle, Frédéric Pont, Sébastien Vergez, Philippe Rochaix, Marie Michelas, Carlos Martínez-Gómez, Camille-Charlotte Balança, Marie Tosolini, Laurence Gladieff, Carlos Gomez-Roca, Jean-Pierre Delord, Christel Devaud, Agnès Dupret-Bories, Alejandra Martinez, Clara-Maria Scarlata, Gwenael Ferron, Eliane Mery, Anna Salvioni, Maha Ayyoub, Jean-Jacques Fournié

المساهمون: Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées, Fournié, jean-jacques, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)

المصدر: JCI Insight
JCI Insight, 2021, 6 (2), ⟨10.1172/jci.insight.142513⟩
JCI Insight, Vol 6, Iss 2 (2021)
JCI Insight, American Society for Clinical Investigation, 2021, 6 (2), ⟨10.1172/jci.insight.142513⟩

مصطلحات موضوعية: Male, 0301 basic medicine, Lymphocyte, [SDV]Life Sciences [q-bio], Lymphocyte Cooperation, Programmed Cell Death 1 Receptor, Immunology, T cells, Gene Expression, Uterine Cervical Neoplasms, Cancer immunotherapy, CD8-Positive T-Lymphocytes, In Vitro Techniques, Biology, Lymphocyte Activation, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Antigens, Neoplasm, Immune Tolerance, medicine, Humans, Cytotoxic T cell, RNA, Messenger, CD154, Ovarian Neoplasms, Immunity, Cellular, Apyrase, T-Lymphocytes, Helper-Inducer, General Medicine, Dendritic cell, Immune checkpoint, Tumor antigen, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Cancer research, Medicine, Female, Tumor Escape, Cytokine secretion, CD8, Research Article

الوصف: International audience; Tumor antigen-specific CD4 T cells accumulate at tumor sites, evoking their involvement in antitumor effector functions in situ. Contrary to CD8 cytotoxic T lymphocyte exhaustion, that of CD4 T cells remains poorly appreciated. Here, using phenotypic, transcriptomic, and functional approaches, we characterized CD4 T cell exhaustion in patients with head and neck, cervical, and ovarian cancer. We identified a CD4 tumor-infiltrating lymphocyte (TIL) population, defined by high PD-1 and CD39 expression, which contained high proportions of cytokine-producing cells, although the quantity of cytokines produced by these cells was low, evoking an exhausted state. Terminal exhaustion of CD4 TILs was instated regardless of TIM-3 expression, suggesting divergence with CD8 T cell exhaustion. scRNA-Seq and further phenotypic analyses uncovered similarities with the CD8 T cell exhaustion program. In particular, PD-1hiCD39+ CD4 TILs expressed the exhaustion transcription factor TOX and the chemokine CXCL13 and were tumor antigen specific. In vitro, PD-1 blockade enhanced CD4 TIL activation, as evidenced by increased CD154 expression and cytokine secretion, leading to improved dendritic cell maturation and consequently higher tumor-specific CD8 T cell proliferation. Our data identify exhausted CD4 TILs as players in responsiveness to immune checkpoint blockade.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8a4d843042bee75d1bda7779727348c6Test
https://hal.science/hal-03365487Test

المؤلفون: Amélie Lusque, Camille Franchet, Victor Sarradin, Thomas Filleron, Florence Dalenc

المصدر: Breast Cancer Research : BCR
Breast Cancer Research, Vol 23, Iss 1, Pp 1-11 (2021)

مصطلحات موضوعية: Oncology, medicine.medical_treatment, Triple Negative Breast Neoplasms, B7-H1 Antigen, Tumor-infiltrating lymphocytes, 0302 clinical medicine, Surgical oncology, Tumor Microenvironment, Hepatitis A Virus Cellular Receptor 2, RC254-282, Triple-negative breast cancer, 0303 health sciences, biology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Middle Aged, Prognosis, Lymphocyte Activation Gene 3 Protein, Neoadjuvant Therapy, Treatment Outcome, 030220 oncology & carcinogenesis, Immunohistochemistry, Female, Immune checkpoint, Research Article, Adult, PD-L1, medicine.medical_specialty, TIM-3, Neoadjuvant chemotherapy, 03 medical and health sciences, Young Adult, Breast cancer, Lymphocytes, Tumor-Infiltrating, Antigens, CD, LAG-3, Internal medicine, medicine, Biomarkers, Tumor, Humans, TILs, 030304 developmental biology, Aged, Retrospective Studies, Chemotherapy, business.industry, medicine.disease, Survival Analysis, Immune microenvironment, biology.protein, business

الوصف: Background The immune microenvironment (IME) of triple-negative breast cancers (TNBCs) and its modulation by neoadjuvant chemotherapy (NACT) remain to be fully characterized. Our current study aims to evaluate NACT-induced IME changes and assess the prognostic value of specific immune biomarkers. Methods Tumor-infiltrating lymphocytes (TILs) were identified from hematoxylin-eosin-stained sections of paired pre- and post-NACT tumor samples from a TNBC cohort (n = 66) and expression of PD-L1, TIM-3, and LAG-3 evaluated by immunohistochemistry. Results Overall TIL counts and PD-L1 expression did not differ pre- and post-NACT, but there was a response-specific statistically significant difference. TIL counts decreased in 65.5% of patients who achieved a pathological complete response (pCR) and increased in 56.8% of no-pCR patients (p = 0.0092). PD-L1 expression was significantly more frequently lost after NACT in pCR than in no-pCR patients (41.4% vs 16.2%, p = 0.0020). TIM-3 positivity (≥ 1%) was significantly more frequent after NACT (p 10%) was significantly associated with better overall survival (OS), p = 0.0112. After NACT, PD-L1 positivity and strong TIM-3 positivity (≥ 5%) were both associated with significantly worse OS (p = 0.0055 and p = 0.0274, respectively). Patients positive for both PD-L1 and TIM-3 had the worst prognosis (p = 0.0020), even when only considering patients who failed to achieve a pCR, p = 0.0479. Conclusions NACT induces significant IME changes in TNBCs. PD-L1 and TIM-3 expression post-NACT may yield important prognostic information for TNBC patients.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::86e577c8b94b938415758ee82e7c4ee2Test
https://pubmed.ncbi.nlm.nih.gov/34039396Test