Generating CAR T cells from tumor-infiltrating lymphocytes.
Ontology highlight
ABSTRACT:
SUBMITTER: Mills JK
PROVIDER: S-EPMC8186112 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Microbial organisms play key roles in numerous physiological processes in the human body and have recently been shown to modify the response to cancer radiotherapy and immune checkpoint inhibitors. Here, we demonstrate that HLA molecules of both glioblastoma tissues as well as tumor cell lines present bacteria-specific peptides. This finding prompted us to examine whether tumor-infiltrating lymphocytes (TILs) recognize intratumoral microbiota. Indeed, bacterial peptides eluted from HLA-DR II molecules are recognized by both TILs, albeit weakly, and peripheral blood-derived memory CD4+ T cells, which, upon stimulation with bacterial peptides, also recognize several tumor antigens. Furthermore, using an unbiased antigen discovery approach for a TIL CD4+ T cell clone (TCC) we show that it recognizes a broad spectrum of peptides from pathogenic bacteria, commensal gut microbiota and also glioblastoma-related tumor antigens. These peptides were strongly stimulatory for bulk TILs and peripheral blood memory cells. Our data hint at how bacterial pathogens and bacterial gut microbiota can be involved in specific immune recognition of tumor antigens.
2023-02-20 | PXD036811 | Pride
Project description:Tumor-infiltrating lymphocytes (TILs) may represent a viable source of T cells for the biological treatment of patients with gliomas. Glioma tissue was obtained from 16 patients, tumor cell lines were established, and TILs were expanded in 16/16 cases using a combination of IL-2/IL-15/IL-21. Intracellular cytokine staining (ICS, IL-2, IL-17, TNFα and IFNγ production) as well as a cytotoxicity assay was used to detect TIL reactivity against autologous tumor cells or shared tumor-associated antigens (TAAs; i.e., NY-ESO-1, Survivin or EGFRvIII). TILs were analyzed by flow cytometry, including T-cell receptor (TCR) Vβ family composition, exhaustion/activation and T-cell differentiation markers (CD45RA/CCR7). IL-2/IL-15/IL-21 expanded TILs exhibited a mixture of CD4+, CD8+, as well as CD3+ CD4-CD8- T cells with a predominant central memory CD45RA-CCR7+ phenotype. TIL showed low frequencies of T cells testing positive for PD-1, TIM-3 and CTLA-4. LAG3 tested positive in up to 30% of CD8+ TIL, with low (1.25%) frequencies in CD4+ T cells. TIL cultures exhibited preferential usage of Vβ families and recognition of autologous tumor cells defined by cytokine production and cytotoxicity. IL-2/IL-15/IL-21 expanded TILs represent a viable source for the cellular therapy of patients with gliomas.
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Project description:Background:Lung cancer stem cells (LCSCs) are endowed with high aldehyde dehydrogenase (ALDH) expression and play roles in tumor proliferation, metastasis, and drug resistance. Their elusive nature may allow them to escape the immune response by tumor-infiltrating lymphocytes (TILs), which can positively affect the outcome in non-small cell lung cancer (NSCLC) patients. Despite independent investigations on both LCSCs and TILs, the relationship between the two has been very marginally considered. We analyzed whether these two cell types may be related as a prerequisite for novel diagnostic and therapeutic approaches. Methods:In this cross-sectional study, NSCLC human surgical specimens from 12 patients were tested by ALDEFLUOR assay to identify ALDHhigh cells. Fluorescence-activated cell sorting (FACS) analyses for CD3+, CD4+, and CD8+ TILs were performed in combination with immunohistochemistry evaluation. Results:Statistically positive correlations were found between ALDH+ and CD8+, and between ALDH+ and CD3+ cells populations; no correlation was found between ALDH+ and CD4+ cells. The expression of CD3+ and CD8+ by cells accounted for 40.1% and 58.7%, respectively, of the variability of ALDH+ cell expression by an R-squared index, which highlights the strong correlation between TILs and LCSCs. Immunohistochemistry revealed 6-25% positive cells. Conclusions:We report a correlation between cytotoxic TILs and LCSCs, which may contribute to the future development of targeted therapies focusing on the different roles of lymphocytes against lung cancer.
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