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1 7 N O V E M B E R 2 0 1 1 I V O L U M E 1 1 8 , N U M B E R 2 0 Blood
| Content Provider | Semantic Scholar |
|---|---|
| Author | Pangault Ramsay Aj, Clear Kelly G. Kalos Bl, Levine Dombret, Hervé Saint-Louis, Hôpital |
| Abstract | increased numbers of these cells including GrzB expression in FL compared with nonmalignant counterpart reactive lymph node tissue. The authors then used 3-D image reconstructions to allow, for the first time, the in situ visualization of CTL lytic immune synapse structures with FL tumor cells. Interestingly, these effector cells did not enter the follicle but were mostly located within the interfollicular space around nod-ules. The co-staining of activated capsase-3 on FL cells that formed cell conjugates with CTLs provides strong evidence for cytotoxic function. This was verified by performing functional cytotoxicity assays using expanded tumor-infiltrated CD8 ϩ T cells (TILs) from FL patients against autologous FL cells pulsed with superantigen (in vitro immunologic assay that stimulates a large proportion of T cells triggering antigen-induced T-cell receptor signaling and effector function). Of interest, this study also reveals that high GrzB expression in CTLs (high GrzB score patient group) correlates with prolonged PFS in FL patients treated with R-chemo compared with the low GrzB score patient cohort. To date, the results of many IHC studies investigating the role of the immune microen-vironment in FL have been contradictory with technical scoring variations between laboratories acknowledged as a potential issue. Laurent et al have overcome this challenge by combining IHC with confocal microscopy, 3-D reconstructed image analysis, and functional cytotoxicity assays. This immunologic approach has identified strong GrzB expression as a biomarker for activated CTLs capable of forming lytic immune synapses and mounting cytotoxic function against autologous tumor cells. There are, however, some important considerations and future study is required to identify biomarkers and targets for enhancing the clinical potential of immunotherapy. Laurent and colleagues al show that autolo-gous CTLs exhibiting a strong GrzB content did not enter the FL nodule. It is possible that a cancer-associated T-cell motility defect or tumor " barrier " may prevent CTLs from infiltrating the intrafollicular tumor site in FL. Moreover, work using purified TILs, confocal imaging, and quantitative image analysis has identified that it is not only expression levels of biomarkers that is important, but also critical whether these proteins can traffic and polarize to the synapse effector site. FL tumor cells were shown to rapidly induce failure of recruitment of cytoskeletal signaling proteins including cytotoxic machinery (Rab27A) to the synapse site in previously healthy CTLs. 5 This profound tumor-induced T-cell immune synapse defect in FL could be repaired by the immunomodulatory drug lenalidomide. The high-quality confocal … |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.bloodjournal.org/content/bloodjournal/118/20/5366.full.pdf?sso-checked=true |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
