Segura Martínez, Laura

Universitat Autònoma de Barcelona. Facultat de Biociències

Castaño, Ángel Raúl

Diposit Digital de Documents de la UAB

Invariant Natural Killer T cells as Anti-Tumour ImmunotherapyLaura Segura Martínez, Biomedical Sciences Bachelor’s Degree,  Autonomous University of Barcelona, SpainAims IntroductionResults• Know in a general way which is the immunologic response when a tumour appears.• Define what natural killer T cells are and their cellular characteristics.• Describe why invariant natural killer T cells would be effective as anti-tumour therapy• Scientific literature search in Pubmed database using as key words: NKT cells or natural killer Tcells, iNKT cells or invariant natural killer T cells, tumour immunology and cancer/ tumourtherapy. Papers were selected for: quality, date of publication and journal impact.• Search in official websites of World Health Organization and Clinical Trials.Cancer is a disease that can affect any part of the body. One defining feature of it is the rapidcreation of abnormal cells that grow beyond their usual limits, and which can then invadeadjoining tissues and spread to other organs.It is one of the most important diseases nowadays because is a leading cause of deathworldwide. The research of new therapies is crucial for helping patients that do not respond toclassical therapies such as radiotherapy, surgery or chemotherapy.It is known that our immune system is able to fight against tumours in a process referred to ascancer immunoediting which involves three phases: elimination, equilibrium and escape.Because of it many immunotherapies are being set to treat tumours. For example, here wedescribe NKT cells and their demonstrated anti-tumour potential.Materials and MethodsCharacterization of NKT cells iNKT cells for Cancer Treatment1. What are NKT cells? NKT cells are a unique subset of lymphocytes that express at thesame time NK cell markers (NK1.1 in mice and CD161 in humans) as well as a TCR α/β, with arestricted repertoire. This TCR recognizes glycolipids presented by CD1d, a non-classical antigenpresenting molecule that associates with β2-microglobulin. The rapid response of this cells totheir antigens is characteristic of an innate immune response, and allows the polarizing cytokines(IFN-γ and/or IL-4) to regulate adaptive immunity.3. Ligands2. SubtypesSynthetic compoundsα-Galactosylceramide (α-GalCer)OCH (analog of α-GalCer)C20:2 (analog of α-GalCer )C-glycoside (analog of α-GalCer)βGalactosylceramide (βGalCer (C12))Bacterial moleculesα-gluconosylceramide (GSL-1)α-galacturonosylceramide (GS-1')Phosphatidylinositol mannoside (PIM)Isoglobotrihexosylceramide (iGb3)Type I NKT cells (iNKT cells)Type II NKT cells NKT-like cellsCD1d dependentYes Yes No α-GalCer reactiveYes No NoTCR Semi-invariant Variant Variant TCR α-chain Vα14-Jα18 (mice)Vα24-Jα18 (humans)Diverse Diverse1. Mechanisms to attack tumour cells•iNKT cells express highlevels of granzyme,perforin and FasL that canproduce cytolysis orligand induced killing oftumour cells.Direct•iNKT cells produce largeamounts of IFN-γ, whichactivates NK cells andCD8+ T cells that havecytotoxic activity ontumour cells.IndirectFigure 2. Anti-tumour immune responses induced by activatediNKT cells. After activation, iNKT cells exert direct anti-tumouractivity, including perforin, granzyme and Fas ligand, and up-regulate CD40L which stimulates CD40 on DC to produce IL-12.EndogenousmoleculesDisialoganglioside (GD3)Phosphatidylinositol (PI)4. ActivationTwo pathways: Activation mediated by cytokines Antigenic activation by TCR signal• Direct: APCs presentation to NKT cells byCD1d-glycolipid antigen complexes.• Indirect: APCs are activated through theirTLRs that trigger the loading of CD1dmolecules with endogenous antigenspresented to NKT cells.6. NKT cells in Regulation of Tumour ImmunityType I NKT cellsPromotion of tumour immunityType II NKT cellsSuppression of tumour immunityTumour Rejection5. Functions and Implications in DiseasesTumoursTransplantation toleranceInfections Allergy AutoimmunityTCR β-chain Diverse Diverse Diverse2. Manipulating iNKT cells for Cancer Immunotherapy Stimulating patient’s own iNKT cells by the administration of exogenous activators• IL-12  this cytokine exerts multiple anti-tumour effects that include the activation of NK, iNKT and Tcells in addition to its immune-cell-independent anti-angiogenic effects to mediate tumour rejection.• α-GalCer  iNKT cells recognize it in conjunction to CD1d. After activation these cells exert potent directand indirect anti-tumour activities, inducing the production of large amounts of cytokines (IL-12 and IFN-γ).• α-GalCer-DCs  the adoptive transfer of α-GalCer-pulsed DCs induce more potent anti-tumour effectsthan the treatment with soluble α-GalCer. Transferring activated iNKT cells to the patient• in vitro activated iNKT cells  iNKT cell populations are isolated from a patient with cancer,selected and expanded in vitro with cytokines before being infused back into the patient. These expandediNKT cell populations can be co-infused with CD1d ligand-pulsed DCs to enhance the anti-tumour activity invivo.• iPS-derived iNKT cells  for patients whose NKT cells are limited, induced pluripotent stem cells canbe generated , developed into functional iNKT cells in vitro and then injected to the patient. This cells havedemonstrated to suppress tumour growth in vivo.3. Clinical trials done with this therapyAccording to ClinicalTrials.gov nowadays there are 138 studies working with NKT cells to treatcancer around the world.Conclusions• NKT cells express NK cell markers and at the same time TCRs α/β with a restricted repertoire thatrecognizes CD1d. They can be divided then into three subsets: type I NKT cells (or iNKT cells), type IINKT cells and NKT-like cells. Once these cells become activated by endogenous or exogenous ligands,they mediate immunoregulatory functions in different diseases such as cancer. In this case, type I NKTcells potentiate the anti-tumour response, while type II NKT cells suppress this response.• iNKT cells, characterized by its semi-invariant TCR and by its specific recognition of α-GalCerpresented by CD1d, can attack the tumour by indirect mechanisms (releasing cytokines like IFN-γ thatactivate other effector cells as NK cells or CTLs) or direct mechanisms (by their own cytotoxicactivities).• To use iNKT cells for cancer treatment we can stimulate the patient's own cells with theadministration of exogenous activators (IL-12 or α-GalCer) or we can transfer in vitro activated iNKTcells to the patient.• By the moment, there are a lot of clinical trials and research groups working on this promising newtherapy with iNKT cells, so it is to hope that their optimal and safe therapeutic use will be as rapidlyand efficiently defined as have been defined their various roles and activities and we hope too thatiNKT-cell based immunotherapies in combination or not with other standard therapies could beestablished in the near future.Large amounts of IFN-γ secreted by iNKT cells induce NK cells andCD8+ T cells to exert indirect anti-tumour responses.Figure 3.  Map showing where clinical trials with NKT cells to treat cancer are being done. https://clinicaltrials.gov/ct2/results/map?term=%22natural+killer+T+cells%22+AND+%22cancer%22 Figure 1. Schematic view of the interaction between the TCR of a NKT celland the CD1d molecule presenting a glycolipid antigen.These are being done with patients withhematological cancers which usuallyexpress CD1d and also with solidtumours that do not express CD1d dueto the ability of iNKT cells to attack bothtypes of cancers.Some of the results show that thetherapy is safe, generates iNKT cell-specific responses and haveimmunomodulatory effects in cancerpatients.

Invariant natural killer T cells as anti-tumour immunotherapy

http://ddd.uab.cat/pub/tfg/2014/126443/TFG_LauraSeguraMartinez.pdf

Invariant natural killer T cells as anti-tumour immunotherapy

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