医学免疫学课件：γδ-T细胞临床应用

1、 T Cell Clinical ApplicationTwo distinct lineages of thymocytes are produced in the thymus.In the fully developed thymus, immature double-negative T cells constitute about 60% of the thymocytes. about 20% of the double-negative cells, comprises cells that have rearranged and are expressing the genes

2、 encoding the : T-cell receptor; another 20% of all double negative thymocytes, includes cells bearing : T-cell receptors of very limited diversity. These cells also express the NK1.1 receptor commonly found on NK cells; they are therefore known as invariant NKT cells (iNKT cells)The development of

3、thymocytesSpecification of T cell fateT-cell receptor - and -chain gene rearrangement and expressionT-cell receptor - and -chain gene rearrangement Differences between T cell and T cellClassificationsTwo major subsets V9 V2 T cell Majority of peripheral-blood T lymphocytesDefense against microbial p

4、athogens and tumor cellsV1 T cellResident mainly within mucosal surfaces and epitheliaDefense against infections or malignanciesTumor cell ligands recognized by human T cellsDieter Kabelitz et al. Cancer Res 2007;67:5-8Clinical AppilicationsCancer immunotheropyV9 V2 T cell Cytokines (IFN-, TNF-, IL-

5、17) Chemokines Cytotoxicity Antibody dependent cellular cytotoxicity (ADCC)Bio marker V1 Treg cell T cell immunotheropyVSNon small cell lung cancer (NSCLC)Phase I clinical studyTwo pathwaysDirect in vivo activation of V9V2 T cellsAdoptive transfer of ex vivo expanded V9V2 T cells Transl Lung Cancer

6、Res. 2014 Feb; 3(1): 2333. Tumor cell ligands recognized by human T cells. T cell cytotoxicityGreen- T cellsRed-lung cancer cell lineStrategies for T cell based immunotherapyClinical results of adoptive T cell transfer therapy Median survival of 589 days Median progression-free survival of 126 daysW

7、ith gefitinib (250 mg/d) or docetaxel (60 mg/m2)Median progression-free survival was two months Safe and feasible in patients with NSCLCClinical results of adoptive T cell transfer therapy Proliferation ability of T cell in vitroLittle is known about negative regulation by T cells in human disease1

8、Treg cell infiltration and accumulation in breast tumor sitesIntratumoral T cell numbersPositively correlated withadvanced tumor stages, HER2 expression status, high lymph node metastasisInversely correlated withrelapse-free survival and overall survivalIntratumoral T cellsPositively correlated with

9、FOXP3+ cells and CD4+ T cellsNegatively correlated withCD8+ T cells 1 Treg cell AS Prognostic biomarkerAccumulation of T cells in breast cancer but not in normal breast tissuesChunling Ma et al. J Immunol 2012;189:5029-5036Accumulation of T cells in breast cancer but not in normal breast tissuesCorr

10、elations between , CD4+, CD8+ T cells, and FOXP3+ cellsChunling Ma et al. J Immunol 2012;189:5029-5036Comparison of T cell and FOXP3+ cellon the level of OS and RFSComparison of T cell and FOXP3+ cellconsidering the mortality and relapseFuture directionsImmunotherapyCombinations of this newly emergi

11、ng therapy with established treatmentsEfficacy of T cell transfer therapy should be evaluatedActivation of T cell should be promotedPrognostic biomarker Identification of mechanisms responsible for the accumulation of T cells in breast tumor microenvironmentUnderstanding of the immunosuppressive mec

12、hanisms used by these tumor-derived TregsBlock trafficking and recruitment of Tregs and to reverse the immune suppression mediated by TregsNew research about T cells T cell activation by bispecific antibodiesEpigenetic and transcriptional regulation of T cell differentiationHIV-1-induced impairment

13、of dendritic cell cross talk with T lymphocytesActivated skin T-cells regulate T-cell infiltration of the wound site after burnReferenceKakimi K, Matsushita H, Murakawa T, et al. T cell therapy for the treatment of non-small cell lung cancer. Transl Lung Cancer Res. 2014;3:2333.Ma C, Zhang Q, Ye J,

14、et al. Tumor-infiltrating T lymphocytes predict clinical outcome in human breast cancer. J Immunol. 2012 Nov 15;189(10):5029-36. Kabelitz D, Wesch D, He W. Perspectives of gammadelta T cells in tumor immunology. Cancer Res. 2007 Jan 1;67(1):5-8.Wilhelm M, Smetak M, Schaefer-Eckart K, et al. Successful adoptive transfer and in vivo expansion of haploidentical T cells. J Transl Med. 2014 Feb 15;12:45. doi: 10.1186/1479-5876-12-45.Mateusz L, David KC, Andrew