mTOR-dependent translation drives tumor infiltrating CD8+ effector and CD4+ Treg cells expansion

We performed a systematic analysis of the translation rate of tumor-infiltrating lymphocytes (TILs) and the microenvironment inputs affecting it, both in humans and in mice. Measurement of puromycin incorporation, a proxy of protein synthesis, revealed an increase of translating CD4+ and CD8+ cells in tumors, compared to normal tissues. High translation levels are associated with phospho-S6 labeling downstream of mTORC1 activation, whereas low levels correlate with hypoxic areas, in agreement with data showing that T cell receptor stimulation and hypoxia act as translation stimulators and inhibitors, respectively. Additional analyses revealed the specific phenotype of translating TILs. CD8+ translating cells have enriched expression of IFN-γ and CD-39, and reduced SLAMF6, pointing to a cytotoxic phenotype. CD4+ translating cells are mostly regulatory T cells (Tregs) with enriched levels of CTLA-4 and Ki67, suggesting an expanding immunosuppressive phenotype. In conclusion, the majority of translationally active TILs is represented by cytotoxic CD8+ and suppressive CD4+ Tregs, implying that other subsets may be largely composed by inactive bystanders.

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Review for "Relationship between T cell receptor clonotype and PD‐1 expression of tumor‐infiltrating lymphocytes in colorectal cancer"

10.1002/eji.201948399/v2/review1 ◽

2020 ◽

Author(s):

Lei Zhang

Keyword(s):

Colorectal Cancer ◽

T Cell ◽

T Cell Receptor ◽

Tumor Infiltrating Lymphocytes ◽

Cell Receptor ◽

Infiltrating Lymphocytes

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Ανοσοθεραπεία ενάντια στον καρκίνο του παγκρέατος

10.12681/eadd/48459 ◽

2020 ◽

Author(s):

Παύλος Παπακοτούλας

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Tumor Infiltrating Lymphocytes ◽

Ciclopirox Olamine ◽

Ifn Γ ◽

Infiltrating Lymphocytes

Το πιο συχνό είδος καρκίνου του παγκρέατος είναι το αδενοκαρκίνωμα του παγκρέατος. Το παγκρεατικό αδενοκαρκίνωμα είναι η 4η κύρια αιτία των θανάτων από καρκίνο παγκοσμίως. Περίπου 60-80% των ασθενών έχουν τη στιγμή της διάγνωσης προχωρημένη νόσο, επειδή ο καρκίνος εισβάλλει στους περιβάλλοντες ιστούς έξω από το πάγκρεας (τοπικά προχωρημένος), ή έχει δώσει μεταστάσεις έξω από το πάγκρεας (μεταστατικός). Καθώς η νόσος παρουσιάζει πολύ υψηλό ποσοστό θνητότητας, κρίνεται επιτακτική η ανάγκη ανεύρεσης νέων αποτελεσματικότερων θεραπειών. Με τη ανάπτυξη της μοριακής και βιολογικής κατανόησης της ογκογενετικής εξέλιξης, εφαρμόστηκαν νέες στρατηγικές στην αντιμετώπιση του καρκίνου και κατ’ επέκταση σε αυτόν της ανοσοθεραπείας του καρκίνου. Η κατανόηση των μοριακών μηχανισμών που διέπουν την ανοσοδιαφυγή των όγκων, αλλά και την αλληλεπίδραση των καρκινικών κυττάρων με τα κύτταρα του ανοσοποιητικού συστήματος, έχει δώσει τεράστια ώθηση στην ανοσοθεραπεία του καρκίνου την τελευταία δεκαετία. Τα κύτταρα του ανθρώπινου οργανισμού βρίσκονται υπό διαρκή ανοσιακή επιτήρηση και το ανοσοποιητικό σύστημα αποτελεί αποτρεπτικό μηχανισμό στον νεοπλασματικό μετασχηματισμό και τη δημιουργία νεοπλασιών. Κλινικό σημείο που επιβεβαιώνει τη θεωρία της ανοσοεπιτήρησης είναι η διαπίστωση της παρουσίας CD8+ T-λεμφοκυττάρων μέσα στους όγκους (Tumor Infiltrating Lymphocytes – TILs). Συνέπεια αυτού είναι και οι θεραπείες που βασίζονται στην καταστολή των σημείων ελέγχου του ανοσοποιητικού συστήματος (Immune Checkpoint Inhibitors). Είναι γνωστό ότι φάρμακα με αντιμυκητιακές ιδιότητες συμβάλλουν στην ενίσχυση του ανοσοποιητικού συστήματος. Ένα χαρακτηριστικό παράδειγμα είναι η κυκλοπιροξολαμίνη (Ciclopirox Olamine, CPX), που χορηγείται σε άτομα που ταλαιπωρούνται από μυκητιάσεις. Σύμφωνα με την παρούσα διατριβή η συγκεκριμένη θεραπεία μπορεί να μειώσει δραστικά την ταχύτητα εξέλιξης των καρκινικών όγκων, αλλά παράλληλα ενισχύει τη δράση των κυτταροστατικών που χορηγούνται στον ασθενή. Επίσης, η τινζαπαρίνη (Ηπαρίνη Χαμηλού Μοριακού Βάρους) χρησιμοποιείται για την πρόληψη και την αντιμετώπιση της φλεβικής θρομβοεμβολής, αλλά από τα αποτελέσματα της παρούσης διατριβής φαίνεται ότι μπορεί να διαδραματίζει ρόλο στην αντιμετώπιση του όγκου. Οι μηχανισμοί στους οποίους οφείλονται τα σημαντικά in vivο αποτελέσματα, είναι η αύξηση της IFN-γ, η αύξηση των CD8+ κυττάρων, η μείωση των Tregs κυττάρων, η μείωση της έκφρασης του VEGFR-2 και η αύξηση της απόπτωσης στα καρκινικά κύτταρα. Στην παρούσα διατριβή, προτείνεται πως η συνδυαστική θεραπεία με τη συμμετοχή της ανοσοθεραπείας, έχει προφανώς υψηλότερη αντινεοπλασματική επίδραση στη μείωση της ανάπτυξης του όγκου, υποδηλώνοντας μια συνεργική δράση. Αυτή η συνεργική στρατηγική μπορεί να ανοίξει νέους δρόμους για τη θεραπεία ασθενών με καρκίνο του παγκρέατος.

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CD38 Correlates with an Immunosuppressive Treg Phenotype in Lupus-Prone Mice

International Journal of Molecular Sciences ◽

10.3390/ijms222111977 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11977

Author(s):

Jocelyn C. Pérez-Lara ◽

Enrique Espinosa ◽

Leopoldo Santos-Argumedo ◽

Héctor Romero-Ramírez ◽

Gabriela López-Herrera ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Immune Activation ◽

Lupus Erythematosus ◽

Clinical Signs ◽

Foxp3 Expression ◽

Cell Receptor ◽

Treg Cells ◽

Transmembrane Glycoprotein ◽

Ifn Γ

CD38 is a transmembrane glycoprotein expressed by T-cells. It has been reported that patients with systemic lupus erythematosus (SLE) showed increased CD38+CD25+ T-cells correlating with immune activation and clinical signs. Contrariwise, CD38 deficiency in murine models has shown enhanced autoimmunity development. Recent studies have suggested that CD38+ regulatory T-cells are more suppressive than CD38− regulatory T-cells. Thus, we have suggested that CD38 overexpression in SLE patients could play a role in regulating immune activation cells instead of enhancing it. This study found a correlation between CD38 with FoxP3 expression and immunosuppressive molecules (CD69, IL-10, CTLA-4, and PD-1) in T-cells from lupus-prone mice (B6.MRL-Faslpr/J). Additionally, B6.MRL-Faslpr/J mice showed a decreased proportion of CD38+ Treg cells regarding wild-type mice (WT). Furthermore, Regulatory T-Cells (Treg cells) from CD38-/- mice showed impairment in expressing immunosuppressive molecules and proliferation after stimulation through the T-cell receptor (TCR). Finally, we demonstrated an increased ratio of IFN-γ/IL-10 secretion in CD38-/- splenocytes stimulated with anti-CD3 compared with the WT. Altogether, our data suggest that CD38 represents an element in maintaining activated and proliferative Treg cells. Consequently, CD38 could have a crucial role in immune tolerance, preventing SLE development through Treg cells.

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Prolongation of survival following depletion of CD4+CD25+ regulatory T cells in mice with experimental brain tumors

Journal of Neurosurgery ◽

10.3171/jns.2006.105.3.430 ◽

2006 ◽

Vol 105 (3) ◽

pp. 430-437 ◽

Cited By ~ 101

Author(s):

Abdeljabar El Andaloussi ◽

Yu Han ◽

Maciej S. Lesniak

Keyword(s):

Immune Response ◽

T Cells ◽

Brain Tumors ◽

Malignant Gliomas ◽

Tumor Infiltrating Lymphocytes ◽

Treg Cells ◽

Separate Experiment ◽

The Central Nervous System ◽

Novel Target ◽

Infiltrating Lymphocytes

Object Regulatory CD4+CD25+ T cells have been shown to play an important role in the regulation of the immune response. Whereas the presence of these cells has been associated with immune suppression, the lack of regulatory T (Treg) cells has been shown to induce autoimmunity. The purpose of this study was to define the role of Treg cells in tumors of the central nervous system (CNS). Methods The authors implanted syngeneic GL261 tumor cells in the brains or flanks of C57BL/6 mice. The resulting tumors were later removed at specific time points, and the presence of tumor-infiltrating lymphocytes was analyzed by performing flow cytometry for the presence of Treg cells. In a separate experiment, mice with GL261 tumors were treated with injections of anti-CD25 monoclonal antibody (mAb) to determine whether depletion of Treg cells may have an impact on the length of survival in mice with brain tumors. Tumor-infiltrating lymphocytes isolated from mice with GL261 tumors were found to have a significant increase in the presence of Treg cells compared with control lymphocytes (p < 0.05). Moreover, Treg cells isolated in murine brain tumors expressed FoxP3, CTLA-4, and CD62L. Mice treated with anti-CD25 mAb lived significantly longer than tumor-bearing control animals (p < 0.05). An analysis of brains in surviving animals showed a depletion of CD4+CD25+ T cells. Conclusions The results of this study indicate that CD4+CD25+ Treg cells play an important role in suppressing the immune response to CNS tumors. These Treg cells may therefore represent a potentially novel target for immunotherapy of malignant gliomas.

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T-cell receptor V-gene usage in neoplasms of the central nervous system

Journal of Neurosurgery ◽

10.3171/jns.1993.78.4.0630 ◽

1993 ◽

Vol 78 (4) ◽

pp. 630-637 ◽

Cited By ~ 5

Author(s):

Adrian Merlo ◽

Luis Filgueira ◽

Markus Zuber ◽

Antonio Juretic ◽

Felix Harder ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Tumor Infiltrating Lymphocytes ◽

Cell Receptor ◽

Gene Products ◽

Peripheral Blood Mononuclear ◽

Infiltrating Lymphocytes

✓ The use of tumor-infiltrating lymphocytes in the treatment of central nervous system (CNS) neoplasms has met with serious obstacles due to difficulty of culture and poor characterization. Since in other tumors the therapeutic effects of tumor-infiltrating lymphocytes have been shown to rely on T-cell receptor engagement, the authors addressed the question as to whether expression of T-cell receptor variable (V) domains in cultured tumor-infiltrating lymphocytes from CNS is different from that of autologous cultured peripheral blood mononuclear cells. Infiltrating lymphocytes from CNS neoplasms, including primary malignancies, metastatic cancers, and meningiomas, were cultured in the presence of interleukin-2 and anti-CD3 monoclonal antibodies (MoAb's) in order to obtain optimum growth of T cells. Autologous peripheral blood mononuclear cells from the same patients were similarly cultured. After 4 to 5 weeks of culture, 97.3% ± 2.6% (mean ± standard deviation) of the resulting cell populations were CD3-positive lymphocytes. The expression of T-cell receptor V domains was then studied by using a panel of 12 MoAb recognizing gene products from T-cell receptor V-α 2, V-β 5, 6, 8, and 12, V-γ 4 and 9 families, and from two subfamilies of V-δ 2. Remarkably, in over 70% of all paired measurements, percentages of T cells expressing discrete T-cell receptor V-gene products were found to be virtually identical in tumor- and peripheral blood-derived cultured cell populations, with differences never exceeding 1%. In contrast, a different expression of individual V-gene products, concerning both α/β and γ/δ T-cell receptors, could be detected between cultured tumor-infiltrating lymphocytes and autologous peripheral blood-derived T lymphocytes in seven of 12 patients. In two cases, significant differences between the two populations were also observed in the proliferative responses obtained upon stimulation with staphylococcal enterotoxins that trigger defined V-β T-cell receptors. Altogether, these data suggest that the T-cell receptor repertoire of cultured tumor-infiltrating lymphocytes from CNS tumors, suitable for use in adoptive immunotherapies, differs from that of autologous cultured peripheral blood mononuclear cells.

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Mesenchymal stromal cell plasticity and the tumor microenvironment

Emerging Topics in Life Sciences ◽

10.1042/etls20170141 ◽

2017 ◽

Vol 1 (5) ◽

pp. 487-492

Author(s):

Hee Joon Bae ◽

Shutong Liu ◽

Ping Jin ◽

David Stroncek

Keyword(s):

Tumor Microenvironment ◽

Transforming Growth Factor ◽

Critical Role ◽

Tumor Infiltrating Lymphocytes ◽

Transforming Growth Factor Β ◽

Interferon Γ ◽

Tnf Α ◽

Ifn Γ ◽

Factor Α ◽

Infiltrating Lymphocytes

Mesenchymal stem cells or mesenchymal stromal cells (MSCs) are a multipotent, heterogeneous population of cells that play a critical role in wound healing and tissue regeneration. MSCs, found in the tumor microenvironment, support tumor growth through the production of angiogenic factors, growth factors and extracellular matrix proteins. They also have immunomodulatory properties, and since they produce indoleamine 2,3-dioxygenase (IDO), prostaglandin E2 (PGE2) and transforming growth factor β (TGF-β), they have been thought to have primarily immunosuppressive effects. However, their role in the tumor microenvironment is complex and demonstrates plasticity depending on location, stimulatory factors and environment. The presence of melanoma-activated tumor-infiltrating lymphocytes (TILs) has been shown to produce pro-inflammatory changes with TH1 (type 1T helper)-like phenotype in MSCs via activated-TIL released cytokines such as interferon γ (IFN-γ), tumor necrosis factor α (TNF-α) and interleukin-1α (IL-1α), while simultaneously producing factors, such as IDO1, which have been traditionally associated with immunosuppression. Similarly, the combination of IFN-γ and TNF-α polarizes MSCs to a primarily TH1-like phenotype with the expression of immunosuppressive factors. Ultimately, further studies are encouraged and needed for a greater understanding of the role of MSCs in the tumor microenvironment and to improve cancer immunotherapy.

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