ABSTRACT
Targeting T cell receptor ß-chain constant region 1 (TRBC1) CAR-T could specifically kill TRBC1+ T-cell malignancies. However, over-expressed CARs on anti-TRBC1 CAR transduced TRBC1+ T cells (CAR-C1) bound to autologous TRBC1, masking TRBC1 from identification by other anti-TRBC1 CAR-T, and moreover only the remaining unoccupied CARs recognized TRBC1+ cells, considerably reducing therapeutic potency of CAR-C1. In addition, co-culture of anti-TRBC1 CAR-T and TRBC1+ cells could promote exhaustion and terminal differentiation of CAR-T. These findings provide a rationale for pre-depleting TRBC1+ T cells before anti-TRBC1 CAR-T manufacturing.
Subject(s)
Cytotoxicity, Immunologic/immunology , Immunotherapy, Adoptive/methods , Leukemia, T-Cell/therapy , Lymphocyte Depletion/methods , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes/immunology , Animals , Apoptosis , Cell Proliferation , Humans , Leukemia, T-Cell/immunology , Leukemia, T-Cell/metabolism , Leukemia, T-Cell/pathology , Mice , Mice, Inbred NOD , Mice, SCID , Receptors, Chimeric Antigen/immunology , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Intratumor heterogeneity (ITH) of T cell receptor (TCR) repertoire in different T-cell subsets and locations in lung adenocarcinomas was unclear. Here, we investigated percentages and TCR repertoire of freshly isolated CD4+ and CD8+ tumor infiltrating lymphocytes (TILs) in tumor centers and margins by flow cytometry on 80 tumor samples from 20 patients and high-throughput TCR sequencing on 27 and 25 samples of CD4+ and CD8+ TILs from seven patients. Our results demonstrated that amount and TCR repertoire diversity of CD4+ TILs were significantly higher than those of CD8+ TILs and moreover substantial ITH regarding amount and TCR repertoire of CD4+ and CD8+ TILs were observed. Additionally, ITH of CD4/CD8 T-cell ratio and CD8+ TIL repertoire across center regions was lower than that across margin regions. The amount and TCR repertoire ITH of CD4+ and CD8+ TILs and mean clonality of CD8+ TILs in tumor centers were associated with relapse. Our study provides insights into amount and TCR repertoire ITH of CD4+ and CD8+ TILs in tumor centers and margins as well as corresponding association with prognosis in lung adenocarcinoma patients, suggesting potential clinical significance of TCR repertoire.
Subject(s)
Adenocarcinoma/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Lung Neoplasms/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Receptors, Antigen, T-Cell/immunology , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Aged , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Female , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Lymphocytes, Tumor-Infiltrating/metabolism , Male , Margins of Excision , Middle Aged , Neoplasm Recurrence, Local , Prognosis , Receptors, Antigen, T-Cell/metabolism , Survival AnalysisABSTRACT
Preoperative chemotherapy could decrease tumor size and improve overall survival for esophageal squamous cell carcinoma (ESCC), and moreover, rational combination of chemotherapy and immunotherapy could increase likelihood of inducing an effective antitumor immune response. However, the immunologic impact of chemotherapeutic drugs originally chosen for cancer treatment due to the direct toxicity is poorly understood. We assess the effect of a combination of clinically approved chemotherapeutic drugs [paclitaxel-nedaplatin (PTX-NDP)] on T-cell receptor (TCR) repertoires of peripheral T cells and tumor-infiltrating lymphocytes (TILs) from five patients with primary ESCC. We found that PTX-NDP therapy induced immediate and substantial changes in clonotype frequencies of peripheral T cells and TILs, and moreover, compared with clonal amplification, clonal contraction was more likely to occur in more abundant clones in patients with ESCC. Significant increases in TCR diversity were observed in peripheral T cells but not in TILs after PTX-NDP therapy. Reconstruction of posttreatment TILs was not merely a result of local expansion or contraction of pretreatment TILs, but also-at least in part-a consequence of the migration of peripheral T cells into the chronically inflamed tumor microenvironment. Our findings uncover further insight into T-cell immune response modulated with chemotherapy, providing for theoretical bases for rational combination strategy of chemotherapy and immunotherapy.
