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Lymphocyte infiltration in breast tumors has a positive prognostic value, presumably because some of these lymphocytes have an anti-tumor activity. The aim of this work was to obtain evidence for the presence of tumor-specific CD8+ T cells in tumor infiltrating lymphocytes (TILs) from primary breast carcinomas. We isolated TILs from five tumors and derived 80-170 CD8+ T cell clones per tumor. We analyzed their diversity by sequencing the CDR3 region of the TCRß chain. Cd8+ TILs are oligoclonal but it's not necessarily related to the tumor. It can be due to the presence of memory T cells to viral and other antigens. We tested all these T cell clones for recognition of candidate mutated peptides, selected on the basis of exome and RNA sequencing of the tumors. For 3 tumors we screened also for recognition of MAGE- or ERBB2- derived peptides. We detected anti-tumor CD8+ T cell clones that recognized mutated peptides in one tumor: out of 57 tested clonotypes, 6 recognized 4 mutated peptides. One clonotype was represented by 2 independent clones, while the 5 other clonotypes were represented by one clone. For each mutated peptide, we identified the presenting HLA molecule and confirmed antigen processing. These results indicate that some primary breast carcinomas are immunogenic. The corresponding patient could benefit from immunotherapy. Notre laboratoire s'intéresse à l'immunogénicité des carcinomes mammaires primaires. Nous savons que l'infiltration lymphocytaire dans des tumeurs du sein est associée à un meilleur pronostic des patientes. Mais l'existence de T anti-tumoraux qui reconnaissent des antigènes spécifiques de tumeurs n’a jamais été montrée. Le but du travail est de documenter l'existence de lymphocytes T cos+ qui infiltrent des carcinomes mammaires primaires et qui reconnaissent des antigènes spécifiques des tumeurs. Dans ce but, des lymphocytes T cos+ ont été extraits de S carcinomes primaires, puis clonés. Nous récupérons entre SO et 170 clones par tumeur. L'exome tumoral est séquencé et l'expression des gènes est analysée grâce au séquençage de l'ARN tumoral. Les clones T sont testés pour la reconnaissance de peptides antigéniques codés par des gènes mutés, codés par des gènes MAGE ou codé par le gène ERBB 2 s'ils sont exprimés dans la tumeur. Nous avons également analysé la diversité de ces clones par séquençage de la partie CDR3 de la chaine f3 du TCR. Nous observons une oligoclonalité avec des clonotypes répétés parmi les clones T extraits des tumeurs mais également parmi les clones T présents dans du tissu mammaire normal. Cela peut être dû à la présence de lymphocytes T mémoire antiviraux ou dirigés contre d'autres antigènes. Parmi les S tumeurs analysées, nous n'avons détecté des clones T cos+ dirigés contre des antigènes mutés que dans une seule d'entre elles. Sur 57 clonotypes testés, 6 clonotypes dont un qui est répété deux fois, reconnaissent 4 peptides mutés. Nous avons identifié le complexe HLA-peptide reconnu par chacun des clones et confirmé 1'apprêtement antigénique des peptides. Pour cette tumeur, 10% des clonotypes sont anti-tumoraux, ce qui suggère qu'il y a eu une réponse immunitaire spontanée au sein de la tumeur. Ces données démontrent que certains carcinomes primaires du sein sont immunogéniques et que les patientes pourraient être traitées par des anticorps du type anti-PD-1 qui ont pour effet de stimuler le système immunitaire.

CD8-Positive T-Lymphocytes --- Carcinoma --- Breast Neoplasms

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Aging --- Autoimmunity --- CD8-Positive T-Lymphocytes --- immunology --- cytology

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Some T lymphocytes were described as CD8-independent, because they can be activated without the CD8 co-receptor cross-linking with the HLA class I molecules. We isolated CD8-independent CTL clones to study the ability of these CTL to bind a tetramer either at rest or after stimulation. A mutated tetramer carrying two mutations in the 3 domain of the HLA molecules at the contact site with CD8, was used to isolate a CD8-independent anti-MelanA CTL clone. By screening the laboratory's collection of CTL, an anti-MAGE10 clone was also identified as being CD8-independent. At rest, these two clones can bind to both mutated and non-mutated tetramer and the intensity of staining is similar in presence or absence of a blocking anti-CD8 antibody. Previous research in the laboratory indicated that the majority of recently stimulated CD8 T lymphocytes have a reduced capacity to bind to tetramers and to produce cytokines. The suggested explanation is that the TCR and CD8 molecules are not colocalized on the cell surface of these dysfunctional T cells. The CD8-independent CTL clones were used to validate this hypothesis. We studied the staining with a mutated or a non mutated tetramer and tested the production of cytokines from rested or recently stimulated CTL. Staining with the non-mutated tetramer decreased slightly on day 4 compared to day 0 (before stimulation). The production of cytokines remained unchanged. We conclude that the absence of proximity of the TCR and CD8 molecules may be the main explanation for the dysfunction of recently stimulated T cells. The use of FRET (fluorescence resonance energy transfer) technique allows to estimate the proximity between TCR and CD8 molecules and is thus an appropriate technique to identify some anergic T cells in various types of diseases such as cancer or chronic viral diseases. Certains lymphocytes T ont été décrits comme CD8-indépendants parce qu'ils ne nécessitent pas de liaison du co-récepteur CD8 au HLA pour être activés. Nous avons isolé des CTL CD8-indépendants pour étudier leur capacité à se lier à un tétramère, au repos et après stimulation. Un tétramère, doublement muté au site de liaison avec le CD8 dans le domaine 3 du HLA, a été utilisé pour isoler un clone anti-MelanA CD8-indépendant. En criblant la collection de CTL du laboratoire, un clone anti-MAGE10 a aussi été identifié comme étant CD8-indépendant. Au repos, ces deux clones sont marqués par un tétramère non muté et aussi par un tétramère muté. Leur intensité de marquage est similaire en présence ou non d'un anticorps anti-CD8 bloquant. Des travaux au laboratoire ont montré que la plupart des lymphocytes T CD8, dans les jours qui suivent une stimulation, ont une capacité réduite à être marqués par un tétramère et à produire des cytokines. L'explication proposée est que les molécules TCR et CD8 ne sont pas colocalisées à la surface cellulaire de ces lymphocytes T dysfonctionnels. Nos clones CD8-indépendants ont été utilisés pour valider ou infirmer cette hypothèse. Nous avons étudié la capacité de marquage par un tétramère non muté et la production de cytokines des deux clones avant et après stimulation. Comparé à des CTL au repos (jour 0), le marquage par un tétramère non muté ne diminue que faiblement au jour 4 après stimulation et la production de cytokines reste similaire. Nous en concluons que l'absence de proximité des molécules TCR et CD8 serait la cause principale de non fonctionnalité des lymphocytes dans les jours qui suivent une stimulation. L'utilisation du FRET (fluorescence resonance energy transfer) permet d'estimer la proximité entre le TCR et le CD8. Le FRET serait donc une technique adéquate pour identifier des lymphocytes T anergiques dans différents types de maladies telles que cancers ou maladies virales chroniques.

T-Lymphocytes --- CD8-Positive T-Lymphocytes --- Major Histocompatibility Complex --- Genes, MHC Class I --- Genes, MHC Class II

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Medicine. --- positron emission tomography --- head and neck neoplasms --- neovascularization --- pathologic --- PET/CT --- urothelial carcinoma --- bladder cancer --- upper tract urothelial carcinoma --- survival --- PET --- PSMA --- prostate --- DCFPyL --- DCFBC --- PSMA-1007 --- ovarian cancer --- relapse --- SUVmax --- targeted therapy --- prognosis --- soft tissue sarcoma (STS) --- pazopanib --- dynamic 18F-FDG PET/CT --- SUV --- two-tissue compartment model --- magnetic resonance imaging --- machine learning --- diffusion --- perfusion --- texture analysis --- squamous cell carcinoma of the head and neck --- diffusion-weighted imaging --- malignant pleural mesothelioma --- pleural dissemination --- empyema --- pleural effusion --- mCRPC --- SPECT/CT --- Computer-assisted diagnosis --- XOFIGO --- Therapy response assessment --- circulating miRNAs --- breast cancer --- imaging parameters --- PET/MRI --- biomarkers --- triple negative breast cancer --- VCAM-1 --- SPECT imaging --- sdAbs --- Hounsfield unit --- computed tomography --- adipose tissue --- precision oncology --- FDG-PET/CT --- PERCIST --- metastatic breast cancer --- prostate cancer --- 18F-FACBC --- recurrence --- meta-analysis --- review --- meningioma --- somatostatin receptor --- neuroimaging --- radionuclide therapy --- breast --- imaging --- marker --- radiomics --- Yin Yang 1 --- PDAC --- Mesothelin --- noninvasive imaging --- receptor status --- molecular imaging --- nuclear medicine --- guidelines --- overutilization --- epistemology --- consensus --- mantle cell lymphoma --- 18F-FDG PET/CT --- Deauville criteria --- Radium-223 --- FDG --- castrate resistant prostate cancer --- programmed cell death 1 receptor --- diagnostic imaging --- CTLA-4 Antigen --- Immunotherapy --- Adoptive --- radioactive tracers --- radionuclide imaging --- CD8-Positive T-Lymphocytes --- PI-RADS --- diffusion kurtosis imaging --- dynamic contrast-enhanced magnetic resonance imaging --- 68Gallium-PSMA PET/CT --- prostate-specific-antigen --- PSA kinetics thresholds --- biochemical recurrence --- optimal cutoff level --- non-small-cell lung cancer --- circulating tumor cells --- immunotherapy --- response to treatment --- head and neck cancer --- HPV --- EBV --- p16 --- Molecular imaging --- miRNA expression --- radiogenomics --- radiomic --- diagnosis --- biomarker --- glioblastoma --- radiation therapy --- MRI --- diffusion tensor imaging --- Hodgkin lymphoma --- diffuse large B-cell lymphoma --- staging --- response assessment --- locally advanced cervical cancer --- concurrent chemoradiotherapy --- treatment response --- follow up --- cystic tumor --- International Consensus Guidelines --- intraductal papillary mucinous neoplasms --- pancreatic neoplasms --- PD-1 --- PD-L1 --- response to therapy --- NSCLC --- positron-emission tomography --- single-photon emission computed tomography --- immune checkpoint inhibitors --- gold nanoparticle --- heat shock protein 70 --- spectral-CT --- positron emission tomography --- head and neck neoplasms --- neovascularization --- pathologic --- PET/CT --- urothelial carcinoma --- bladder cancer --- upper tract urothelial carcinoma --- survival --- PET --- PSMA --- prostate --- DCFPyL --- DCFBC --- PSMA-1007 --- ovarian cancer --- relapse --- SUVmax --- targeted therapy --- prognosis --- soft tissue sarcoma (STS) --- pazopanib --- dynamic 18F-FDG PET/CT --- SUV --- two-tissue compartment model --- magnetic resonance imaging --- machine learning --- diffusion --- perfusion --- texture analysis --- squamous cell carcinoma of the head and neck --- diffusion-weighted imaging --- malignant pleural mesothelioma --- pleural dissemination --- empyema --- pleural effusion --- mCRPC --- SPECT/CT --- Computer-assisted diagnosis --- XOFIGO --- Therapy response assessment --- circulating miRNAs --- breast cancer --- imaging parameters --- PET/MRI --- biomarkers --- triple negative breast cancer --- VCAM-1 --- SPECT imaging --- sdAbs --- Hounsfield unit --- computed tomography --- adipose tissue --- precision oncology --- FDG-PET/CT --- PERCIST --- metastatic breast cancer --- prostate cancer --- 18F-FACBC --- recurrence --- meta-analysis --- review --- meningioma --- somatostatin receptor --- neuroimaging --- radionuclide therapy --- breast --- imaging --- marker --- radiomics --- Yin Yang 1 --- PDAC --- Mesothelin --- noninvasive imaging --- receptor status --- molecular imaging --- nuclear medicine --- guidelines --- overutilization --- epistemology --- consensus --- mantle cell lymphoma --- 18F-FDG PET/CT --- Deauville criteria --- Radium-223 --- FDG --- castrate resistant prostate cancer --- programmed cell death 1 receptor --- diagnostic imaging --- CTLA-4 Antigen --- Immunotherapy --- Adoptive --- radioactive tracers --- radionuclide imaging --- CD8-Positive T-Lymphocytes --- PI-RADS --- diffusion kurtosis imaging --- dynamic contrast-enhanced magnetic resonance imaging --- 68Gallium-PSMA PET/CT --- prostate-specific-antigen --- PSA kinetics thresholds --- biochemical recurrence --- optimal cutoff level --- non-small-cell lung cancer --- circulating tumor cells --- immunotherapy --- response to treatment --- head and neck cancer --- HPV --- EBV --- p16 --- Molecular imaging --- miRNA expression --- radiogenomics --- radiomic --- diagnosis --- biomarker --- glioblastoma --- radiation therapy --- MRI --- diffusion tensor imaging --- Hodgkin lymphoma --- diffuse large B-cell lymphoma --- staging --- response assessment --- locally advanced cervical cancer --- concurrent chemoradiotherapy --- treatment response --- follow up --- cystic tumor --- International Consensus Guidelines --- intraductal papillary mucinous neoplasms --- pancreatic neoplasms --- PD-1 --- PD-L1 --- response to therapy --- NSCLC --- positron-emission tomography --- single-photon emission computed tomography --- immune checkpoint inhibitors --- gold nanoparticle --- heat shock protein 70 --- spectral-CT

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The issue of Cancers Journal entitled “Role of Medical Imaging in Cancers” presents a detailed summary of evidences about molecular imaging, including the role of computed tomography (CT), magnetic resonance imaging (MRI), single photon emission tomography (SPET) and positron emission tomography (PET) or PET/CT or PET/MR imaging in many type of tumors (i.e. sarcoma, prostate, breast and others), motivating the role of these imaging modalities in different setting of disease and showing the recent developments, in terms of radiopharmaceuticals, software and artificial intelligence in this field. The collection of articles is very useful for many specialists, because it has been conceived for a multidisciplinary point of view, in order to drive to a personalized medicine.

Medicine. --- positron emission tomography --- head and neck neoplasms --- neovascularization --- pathologic --- PET/CT --- urothelial carcinoma --- bladder cancer --- upper tract urothelial carcinoma --- survival --- PET --- PSMA --- prostate --- DCFPyL --- DCFBC --- PSMA-1007 --- ovarian cancer --- relapse --- SUVmax --- targeted therapy --- prognosis --- soft tissue sarcoma (STS) --- pazopanib --- dynamic 18F-FDG PET/CT --- SUV --- two-tissue compartment model --- magnetic resonance imaging --- machine learning --- diffusion --- perfusion --- texture analysis --- squamous cell carcinoma of the head and neck --- diffusion-weighted imaging --- malignant pleural mesothelioma --- pleural dissemination --- empyema --- pleural effusion --- mCRPC --- SPECT/CT --- Computer-assisted diagnosis --- XOFIGO --- Therapy response assessment --- circulating miRNAs --- breast cancer --- imaging parameters --- PET/MRI --- biomarkers --- triple negative breast cancer --- VCAM-1 --- SPECT imaging --- sdAbs --- Hounsfield unit --- computed tomography --- adipose tissue --- precision oncology --- FDG-PET/CT --- PERCIST --- metastatic breast cancer --- prostate cancer --- 18F-FACBC --- recurrence --- meta-analysis --- review --- meningioma --- somatostatin receptor --- neuroimaging --- radionuclide therapy --- breast --- imaging --- marker --- radiomics --- Yin Yang 1 --- PDAC --- Mesothelin --- noninvasive imaging --- receptor status --- molecular imaging --- nuclear medicine --- guidelines --- overutilization --- epistemology --- consensus --- mantle cell lymphoma --- 18F-FDG PET/CT --- Deauville criteria --- Radium-223 --- FDG --- castrate resistant prostate cancer --- programmed cell death 1 receptor --- diagnostic imaging --- CTLA-4 Antigen --- Immunotherapy --- Adoptive --- radioactive tracers --- radionuclide imaging --- CD8-Positive T-Lymphocytes --- PI-RADS --- diffusion kurtosis imaging --- dynamic contrast-enhanced magnetic resonance imaging --- 68Gallium-PSMA PET/CT --- prostate-specific-antigen --- PSA kinetics thresholds --- biochemical recurrence --- optimal cutoff level --- non-small-cell lung cancer --- circulating tumor cells --- immunotherapy --- response to treatment --- head and neck cancer --- HPV --- EBV --- p16 --- Molecular imaging --- miRNA expression --- radiogenomics --- radiomic --- diagnosis --- biomarker --- glioblastoma --- radiation therapy --- MRI --- diffusion tensor imaging --- Hodgkin lymphoma --- diffuse large B-cell lymphoma --- staging --- response assessment --- locally advanced cervical cancer --- concurrent chemoradiotherapy --- treatment response --- follow up --- cystic tumor --- International Consensus Guidelines --- intraductal papillary mucinous neoplasms --- pancreatic neoplasms --- PD-1 --- PD-L1 --- response to therapy --- NSCLC --- positron-emission tomography --- single-photon emission computed tomography --- immune checkpoint inhibitors --- gold nanoparticle --- heat shock protein 70 --- spectral-CT --- n/a