Tumor-Infiltrating Lymphocytes Contain Higher Numbers of Type 1 Cytokine Expressors and DR+ T Cells Compared with Lymphocytes from Tumor Draining Lymph Nodes and Peripheral Blood in Patients with Cancer of the Uterine Cervix

2001 ◽  
Vol 81 (3) ◽  
pp. 424-432 ◽  
Author(s):  
Alessandro D. Santin ◽  
Antonella Ravaggi ◽  
Stefania Bellone ◽  
Sergio Pecorelli ◽  
Martin Cannon ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Uterine Cervix ◽  
Peripheral Blood ◽  
Tumor Infiltrating Lymphocytes ◽  
Patients With Cancer ◽  
Infiltrating Lymphocytes ◽  
Type 1 Cytokine ◽  
Draining Lymph Nodes

scholarly journals Analysis of T-Cell Receptor Vβ Gene Repertoires after Immune Stimulation and in Malignancy by Use of Padlock Probes and Microarrays

2005 ◽  
Vol 51 (4) ◽  
pp. 768-775 ◽  
Author(s):  
Johan Banér ◽  
Per Marits ◽  
Mats Nilsson ◽  
Ola Winqvist ◽  
Ulf Landegren
Keyword(s):  
T Cell ◽  
Lymph Nodes ◽  
Peripheral Blood ◽  
Tumor Infiltrating Lymphocytes ◽  
Staphylococcal Enterotoxin ◽  
Staphylococcal Enterotoxin B ◽  
Padlock Probes ◽  
Enterotoxin B ◽  
Infiltrating Lymphocytes ◽  
Draining Lymph Nodes

Abstract Background: Detection of expanded T-cell clones, identified by their receptor (TCR) repertoires, can assist diagnosis and guide therapy in infectious, inflammatory, and autoimmune conditions as well as in tumor immunotherapy. Analysis of tumor-infiltrating lymphocytes often reveals preferential use of one or a few TCR Vβ genes, compared with peripheral blood, indicative of a clonal response against tumor antigens. Methods: To simultaneously measure the relative expression of all Vβ gene families, we combined highly specific and sensitive oligonucleotide reagents, called padlock probes, with a microarray read-out format. T-Cell cDNA was combined with a pool of Vβ subfamily-specific padlock probes. Reacted probes were selectively amplified and the products hybridized to a microarray, from which the Vβ subfamily distribution in each sample could be determined relative to a control sample. Results: In lymphocytes stimulated with the superantigen staphylococcal enterotoxin B, we detected expansions at the mRNA level of TCR subfamilies previously shown to respond to staphylococcal enterotoxin B. Expansions of the same Vβ families could also be detected by flow cytometry. In samples from two bladder cancer patients, we detected predominant representations of specific Vβ subfamilies in both tumor-infiltrating lymphocytes and in the draining lymph nodes, but not in non-tumor-draining lymph nodes or peripheral blood. Several expression profiles from draining lymph nodes in patients with malignant melanoma were divergent from profiles seen in non-tumor-draining lymph nodes. Conclusion: Padlock probe-based parallel analysis of TCR Vβ gene distributions provides an efficient method for screening multiple samples for T-cell clonal expansions with reduced labor and time of analysis compared with traditional methods.

A Novel Subset of CD8+, CD62L-High Tumor Infiltrating Lymphocytes (TIL) Exhibits Regulatory Function

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3910-3910
Author(s):  
Gregory Plautz ◽  
Li-Xin Wang
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Suppressor Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Regulatory Function ◽  
Effector Cells ◽  
Draining Lymph Node ◽  
Infiltrating Lymphocytes ◽  
Draining Lymph Nodes

Abstract Tumor infiltrating lymphocytes (TIL) have demonstrated therapeutic effects in adoptive cell therapy of melanoma, and there is great interest in optimizing this response. However, the role of lymphocytes during tumor initiation and progression is complex and evolves over time. We have identified two distinct subsets of TIL that have divergent effector vs. regulatory function in murine tumor models. These subsets can be efficiently segregated in vitro based on differential expression of L-selectin (CD62L). Although initially present in small numbers, they can be activated in vitro with anti-CD3 mAb and expanded with a combination of IL-2 and IL-7 to provide sufficient numbers for adoptive transfer into secondary hosts with advanced tumors. Our initial studies demonstrated that the TIL CD62L-low subset is a mixture of CD4 and CD8 cells that individually or in combination mediate tumor-specific regression. By contrast, the CD62L-high subset, which is exclusively CD8+, does not have therapeutic efficacy. Moreover, when CD62Lhigh TIL are co-transferred with CD62L-low effector cells they abrogate their therapeutic efficacy, thus they have suppressor function. Because L-selectin is involved in lymphocyte homing to secondary lymphoid tissues, we hypothesized that the CD62L-high TIL cells might preferentially re-circulate into lymph nodes and inhibit primary sensitization of naïve T cells to tumor antigens. Tumor cells were inoculated subcutaneously, alone or with either CD62L-high TIL or CD62L-low TIL. The CD62L-high TIL actually enhanced the growth of subcutaneous tumors whereas the CD62L-low cells prevented tumor growth. More importantly, tumor-draining lymph nodes were harvested twelve days later and activated in vitro with anti-CD3 and IL-2/IL-7 for adoptive cell transfer to secondary tumor-bearing hosts. The presence of TIL suppressor cells during sensitization of tumor-draining lymph node cells partially inhibited the development of tumor-reactive effector cells. This inhibition was not tumor-antigen specific because TIL suppressor cells derived from the MCA205 fibrosarcoma were able to inhibit sensitization of B16/F10 draining lymph node effector cells. These data suggest that tumors acquire a population of CD8 CD62L-high T cells that can inhibit other effector T cells. The suppressor TIL cells also appear to modulate the tumor stroma to promote tumor growth and modulate antigen-presenting cells that migrate to draining lymph nodes thereby dampening the development of effector cells. Studies are ongoing to determine the mechanism of suppressor function.

scholarly journals Inhibition of caspase-8 activity reduces IFN-gamma expression by T cells from Leishmania major infection

2008 ◽  
Vol 80 (1) ◽  
pp. 129-136 ◽  
Author(s):  
Wânia F. Pereira ◽  
Landi V.C. Guillermo ◽  
Flávia L. Ribeiro-Gomes ◽  
Marcela F. Lopes
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Leishmania Major ◽  
Caspase 8 ◽  
Ifn Gamma ◽  
Major Infection ◽  
Draining Lymph Nodes

Following infection with Leishmania major, T cell activation and apoptosis can be detected in draining lymph nodes of C57BL/6-infected mice. We investigated the mechanisms involved in apoptosis and cytokine expression following Tcellactivation. After two weeks of infection, apoptotic T cells were not detected in draining lymph nodes but activation with anti-CD3 induced apoptosis in both CD4 and CD8 T cells. Treatment with anti-FasLigand, caspase-8 or caspase- 9 inhibitors did not block activation-induced T-cell death. We also investigated whether the blockade of caspase-8 activity would affect the expression of type-1 or type-2 cytokines. At early stages of infection, both CD4 and CD8 T cells expressed IFN-gamma upon activation. Treatment with the caspase-8 inhibitor zIETD-fmk (benzyl-oxycarbonyl-Ile- Glu(OMe)-Thr-Asp(OMe)-fluoromethyl ketone) reduced the proportion of CD8 T cells and IFN-gamma expression in both CD4 and CD8T cells. We conclude that a non apoptotic role of caspase-8 activity may be required for T cell-mediated type-1 responses during L. major infection.

scholarly journals Identification of shared TCR sequences from T cells in human breast cancer using emulsion RT-PCR

2016 ◽  
Vol 113 (29) ◽  
pp. 8272-8277 ◽  
Author(s):  
Daniel J. Munson ◽  
Colt A. Egelston ◽  
Kami E. Chiotti ◽  
Zuly E. Parra ◽  
Tullia C. Bruno ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Bilateral Breast Cancer ◽  
Tumor Infiltrating Lymphocytes ◽  
Specific Response ◽  
Rt Pcr ◽  
Primary Tumors ◽  
Infiltrating Lymphocytes

Infiltration of T cells in breast tumors correlates with improved survival of patients with breast cancer, despite relatively few mutations in these tumors. To determine if T-cell specificity can be harnessed to augment immunotherapies of breast cancer, we sought to identify the alpha–beta paired T-cell receptors (TCRs) of tumor-infiltrating lymphocytes shared between multiple patients. Because TCRs function as heterodimeric proteins, we used an emulsion-based RT-PCR assay to link and amplify TCR pairs. Using this assay on engineered T-cell hybridomas, we observed ∼85% accurate pairing fidelity, although TCR recovery frequency varied. When we applied this technique to patient samples, we found that for any given TCR pair, the dominant alpha- or beta-binding partner comprised ∼90% of the total binding partners. Analysis of TCR sequences from primary tumors showed about fourfold more overlap in tumor-involved relative to tumor-free sentinel lymph nodes. Additionally, comparison of sequences from both tumors of a patient with bilateral breast cancer showed 10% overlap. Finally, we identified a panel of unique TCRs shared between patients’ tumors and peripheral blood that were not found in the peripheral blood of controls. These TCRs encoded a range of V, J, and complementarity determining region 3 (CDR3) sequences on the alpha-chain, and displayed restricted V-beta use. The nucleotides encoding these shared TCR CDR3s varied, suggesting immune selection of this response. Harnessing these T cells may provide practical strategies to improve the shared antigen-specific response to breast cancer.

scholarly journals Tumor infiltrating lymphocytes (TIL) therapy in metastatic melanoma: boosting of neoantigen-specific T cell reactivity and long-term follow-up

2020 ◽  
Vol 8 (2) ◽  
pp. e000848 ◽  
Author(s):  
Joost H van den Berg ◽  
Bianca Heemskerk ◽  
Nienke van Rooij ◽  
Raquel Gomez-Eerland ◽  
Samira Michels ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Metastatic Melanoma ◽  
Peripheral Blood ◽  
Tumor Infiltrating Lymphocytes ◽  
Phase Iii ◽  
Cell Reactivity ◽  
T Cell Reactivity ◽  
Infiltrating Lymphocytes

Treatment of metastatic melanoma with autologous tumor infiltrating lymphocytes (TILs) is currently applied in several centers. Robust and remarkably consistent overall response rates, of around 50% of treated patients, have been observed across hospitals, including a substantial fraction of durable, complete responses.PurposeExecute a phase I/II feasibility study with TIL therapy in metastatic melanoma at the Netherlands Cancer Institute, with the goal to assess feasibility and potential value of a randomized phase III trial.ExperimentalTen patients were treated with TIL therapy. Infusion products and peripheral blood samples were phenotypically characterized and neoantigen reactivity was assessed. Here, we present long-term clinical outcome and translational data on neoantigen reactivity of the T cell products.ResultsFive out of 10 patients, who were all anti-PD-1 naïve at time of treatment, showed an objective clinical response, including two patients with a complete response that are both ongoing for more than 7 years. Immune monitoring demonstrated that neoantigen-specific T cells were detectable in TIL infusion products from three out of three patients analyzed. For six out of the nine neoantigen-specific T cell responses detected in these TIL products, T cell response magnitude increased significantly in the peripheral blood compartment after therapy, and neoantigen-specific T cells were detectable for up to 3 years after TIL infusion.ConclusionThe clinical results from this study confirm the robustness of TIL therapy in metastatic melanoma and the potential role of neoantigen-specific T cell reactivity. In addition, the data from this study supported the rationale to initiate an ongoing multicenter phase III TIL trial.

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