Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function of CD19-specific CAR T-cells via TGF-<strong>β</strong> signaling

doi:10.1007/s11684-023-1010-1

2024, Vol. 18

Issue (1) : 128-146 https://doi.org/10.1007/s11684-023-1010-1

Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function of CD19-specific CAR T-cells via TGF-β signaling

Yuanyuan Hao^1,², Panpan Chen¹, Shanshan Guo¹, Mengyuan Li¹, Xueli Jin¹, Minghuan Zhang¹, Wenhai Deng³, Ping Li⁴, Wen Lei¹(

), Aibin Liang⁴(

), Wenbin Qian¹(

)

¹. Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, China
². Department of Hematology, Henan Provincial People’s Hospital; Zhengzhou University People’s Hospital, Zhengzhou 450003, China
³. Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou 325000, China
⁴. Department of Hematology, Tongji Hospital of Tongji University, Shanghai 200065, China

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Abstract

Tumor-derived exosomes (TEXs) enriched in immune suppressive molecules predominantly drive T-cell dysfunction and impair antitumor immunity. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for refractory and relapsed hematological malignancies, but whether lymphoma TEXs have the same impact on CAR T-cell remains unclear. Here, we demonstrated that B-cell lymphoma-derived exosomes induce the initial activation of CD19–CAR T-cells upon stimulation with exosomal CD19. However, lymphoma TEXs might subsequently induce CAR T-cell apoptosis and impair the tumor cytotoxicity of the cells because of the upregulated expression of the inhibitory receptors PD-1, TIM3, and LAG3 upon prolonged exposure. Similar results were observed in the CAR T-cells exposed to plasma exosomes from patients with lymphoma. More importantly, single-cell RNA sequencing revealed that CAR T-cells typically showed differentiated phenotypes and regulatory T-cell (Treg) phenotype conversion. By blocking transforming growth factor β (TGF-β)–Smad3 signaling with TGF-β inhibitor LY2109761, the negative effects of TEXs on Treg conversion, terminal differentiation, and immune checkpoint expression were rescued. Collectively, although TEXs lead to the initial activation of CAR T-cells, the effect of TEXs suppressed CAR T-cells, which can be rescued by LY2109761. A treatment regimen combining CAR T-cell therapy and TGF-β inhibitors might be a novel therapeutic strategy for refractory and relapsed B-cell lymphoma.

Keywords tumor-derived exosome chimeric antigen receptor T-cell lymphoma TGF-β

Corresponding Author(s): Wen Lei,Aibin Liang,Wenbin Qian

About author:

Li Liu and Yanqing Liu contributed equally to this work.

Just Accepted Date: 13 September 2023 Online First Date: 20 October 2023 Issue Date: 22 April 2024

Cite this article:

Yuanyuan Hao,Panpan Chen,Shanshan Guo, et al. Tumor-derived exosomes induce initial activation by exosomal CD19 antigen but impair the function of CD19-specific CAR T-cells via TGF-β signaling[J]. Front. Med., 2024, 18(1): 128-146.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-1010-1
https://academic.hep.com.cn/fmd/EN/Y2024/V18/I1/128

Fig.1 Characterization and surface markers of exosomes from B-cell malignancies. (A) Size distribution of exosomes from lymphoma cell lines was determined by dynamic light scattering (DLS). (B) Transmission electron micrographs of the exosomes. Scale bars = 200 nm. (C) Western blot for exosome markers (ALIX, TSG101, and CD63) and cellular proteins in Raji–Exo or OCI-LY3–Exo. (D) Flow cytometry analysis of CD19, CD20, and PD-L1 expression on the surfaces of exosomes and their parental tumor cells. The green histograms represent the isotype-matched control mAbs for indicated fluorescent antibodies, whereas the red histograms indicate positive fluorescence. (E) Western blot for determining exosome markers (ALIX, TSG101, and CD63) and TGF-β in exosomes from six patients with B-cell lymphoma. (F) CD19 expression on the surface of exosomes from 18 patients with newly-diagnosed or refractory/relapsed B-cell lymphoma was analyzed through flow cytometry. Data are mean ± S.D.

Fig.2 Priming with CD19-contained lymphoma exosomes activates CD19-specific CAR T-cells. (A) CD19-specific CAR T-cells stained with Hoechst 33 258 (1 μg/mL) were cultured with PKH67-labeled exosomes (100 μg/mL) derived from Raji or OCI-LY3 cells, and the uptake of exosomes was photographed by confocal laser scanning microscopy at 0 and 6 h. Green represents PKH67-labeled exosomes; blue represents CAR T-cells’ nuclei. (B) Killing activity of CAR T-cells that primed with 100 μg/mL Raji–Exo or OCI-LY3–Exo in response to tumor cells. The cytotoxic activity of CAR-T against tumor cells Raji–Luc–GFP was assessed by a luminescence-mediated cytotoxic assay at effector-to-target (E:T) ratios of 10:1, 5:1, 2.5:1, 1.25:1, and 0.625:1 for 4 h. (C) CAR T-cells were cocultured with or without exosomes (100 μg/mL) for 48 h. The concentration of IFN-?, TNF-α, IL-10, IL-6, and IL-4 cytokines in the coculture system were measured by cytometric bead array (CBA) human Th1/Th2 cytokine kit. (D) Flow cytometry analyses the expression of granzyme B in Raji or OCI-LY3 exosome–pretreated CAR T-cells. (E) (a) CAR T-cells (1 × 10⁵ cells) were stained with 1 μmol/L CFSE dye at 37 °C in the dark for 30 min and then treated with Raji or OCI-LY3-exosomes (100 μg/mL) for 48 h. The dilution of CFSE was evaluated through flow cytometry analysis in each group. Flow cytometry analyses the cell cycle (b) and expression of Ki-67 (c) and CD25 and CD69 (d) in the CAR T-cells, which were exposed to indicated exosomes for 48 h. Data are represented as mean ± S.D of three independent biological replicates. P values were obtained from unpaired two-tailed Student’s t-tests. *P < 0.05, **P < 0.01, ***P < 0.001.

Fig.3 Initial activation of CAR T-cells is dependent on exosomal CD19 antigen. (A) The expression of CD19 on the surface of wide-type (Wt) Raji, CD19-KO Raji cells, or their derived exosomes. Red histogram indicates PE-conjugated CD19 antibody fluorescence. The green histogram represents PE isotype Ctrl antibody fluorescence. (B) (a) CFSE-mediated proliferation of CAR-T cocultured with Wt Raji or CD19-KO Raji–Exo was analyzed. Spared CAR-T served as the control. CAR T-cells were exposed to Wt Raji or CD19-KO Raji–Exo for 48 h, and the expression of Ki-67 (b), cell cycle (c), cytotoxicity (d), and the secretion of granzyme B (e) were analyzed. (C) Western blot for exosome marker protein CD63 in Raji–Exo or Raji–Rab27a KO cells (left). Transmission electron micrographs of exosomes in Raji–Exo or Raji–Rab27aKO cells (right). Scale bars = 200 nm. (D) Long-term cytotoxicity of CAR T-cells exposed to Raji–Exo on Raji–Rab27a KO-GFP cells. CAR T-cells were pulsed with the Raji–Exo or not for 48 h and cocultured with Raji–Rab27a KO-GFP cells at an E:T ratio of 1:4 for 5, 10, and 13 days. Flow cytometry analyses the expression of residual GFP⁺ tumor cells at indicated times. (E) In vivo antitumor effect of Raji–Exo-pretreated CAR T-cells. NSG mice were injected intravenously with Raji–Rab27a KO-GFP-luciferase cells (1 × 10⁵) on day −5 and treated with CD19–CAR-T or Raji–Exo-primed CD19–CAR T-cells (1 × 10⁶) on day 0. PBS was injected into the control group. (a) The tumor burden was measured using bioluminescence imaging; (b) Total bioluminescence was traced in CAR-T, Raji–Exo-primed CAR T-cells, and control group; (c) Kaplan–Meier analysis of mice survival curve. Error bars represent SEM. P values were calculated using unpaired two-tailed Student’s t-tests. *P < 0.05, **P < 0.01, ***P < 0.001.

Fig.4 TEXs and plasma exosomes from patients with lymphoma impair the effector functions of CAR T-cells. (A) CAR T-cells were exposed to a dose escalation of the Raji–Exo for 6 h, and cell viability was determined using MTT assay. The expression of 7AAD. (B) TIM-3, LAG-3, and PD-1. (C) and the differentiation of T_CM (CD45RA⁻CD62L⁺), T_Naïve (CD45RA⁺CD62L⁺), T_EFF (CD45RA⁺CD62L⁻), and T_EM (CD45RA⁻CD62L⁻). (D) Analysis by flow cytometry after CAR T-cells were exposed to Raji–Exo for 48 h. (E) CAR T-cells primed with or without Raji–Exo were cocultured in the presence or absence of Raji TEXs with Raji–Luc–GFP cells for 6 h, and a luminescence-mediated cytotoxic assay was performed for cytotoxicity evaluation. CAR T-cells were exposed to plasma exosomes (100 μg/mL) from two patients for 48 h, the expression of TIM-3, LAG-3, and PD-1 (F), and the differentiation of T_CM (CD45RA⁻CD62L⁺), T_Naïve (CD45RA⁺CD62L⁺), T_EFF (CD45RA⁺CD62L⁻), and T_EM (CD45RA⁻CD62L⁻) (G) were analyzed by flow cytometry. (H) CAR T-cells derived from three different patients were cocultured with plasma exosomes (100 μg/mL) from two patients for 48 h and then analyzed through flow cytometry to determine the percent of Tregs (CD4⁺CD25⁺FOXP3⁺). P values were obtained through unpaired two-tailed Student’s t-tests. *P < 0.05, **P < 0.01, ***P < 0.001.

Fig.5 Single-cell transcriptional profiling of CAR T-cells after Raji TEX exposure. (A) The UMAP plot shows the annotation and color codes for cell types of the CAR T-cells derived from three different patients. (B) Heatmap showing the expression of marker genes in the indicated cell types. The top genes are shown on the left. (C) Plot depicts the differences in the proportion of clusters between the CAR T primed with Raji–Exo and untreated CAR T-cells. Red dots indicate that the proportions of these clusters increased in CAR T-cells primed with the Raji–Exo group, and the blue dots mean a decrease. (D) The graphs show the results of a GSEA performed for the indicated gene sets in Raji–Exo-exposed CAR T-cells. The normalized enrichment Score (NES) and false discovery rate (FDR) are indicated.

Fig.6 Analysis of differentially expressed gene related to the T-cell function and phenotype of CAR T-cells after Raji–Exo exposure by single-cell transcriptional profiling. (A) Dot plot illustrates the expression level of genes associated with differentiation, activation, cytotoxicity, proliferation, immune inhibitory, transactions, and chemotaxis in Raji–Exo-exposed CAR T-cell (experiment) and untreated CAR T-cells (control). The size of the circle represents the percentage of cells expressing the gene in each cluster, and the color depicts how highly expressed the gene is within that cluster. (B) Monocle3 trajectory analysis of CAR T-cells. The color represents the stage of cell growth. The black arrow shows the pseudo-time trajectory of the cell growth. (C) The expression of genes (CD69, GZMB, HAVCR2, and LAG3) during the pseudo-time trajectory.

Fig.7 Exosomal transforming growth factor β contributes to the conversion of CAR T-cells into Tregs and terminal differentiated phenotype. (A) UMAP plot shows the expression pattern of FOXP3. Color intensity represents expression level (left). The percentage of FOXP3⁺ cells was shown in the experimental and control groups (Right). (B) Real-time PCR (left) and flow cytometry (right) were performed for the analysis of FOXP3 expression after CAR T-cells were primed with Raji–Exo for 48 h. (C) Expression of TGF-β in Raji–Exo and OCI-LY3–Exo by Western blots analysis. (D) Western blot was performed for the analysis of SMAD3 and p-SMAD3 expression in CAR T-cells cocultured with Raji–Exo in the presence or absence of the TGF-β inhibitor LY2109761 (100 μmol/L). CAR T-cells alone or CAR T-cells cocultured with Raji–Exo in the presence of 0, 25, 50, and 100 μmol/L LY2109761 for 48 h, and then flow cytometry analyses were performed to determine the percentages of Tregs (CD4⁺CD25⁺FOXP3⁺) (E), T_EFF (CD62L⁻CD45RA⁺) (F), and the expression of LAG-3, TIM-3, and PD-1 (G). CAR T-cells were cocultured with Raji–Exo and PD-1 inhibitor (IBI308, 30 μg/mL) or LAG3 inhibitor (SHR-1702, 40 μg/mL) for 48 h, and the expression levels of LAG3, TIM3, and PD-1 on the surfaces of CAR T-cells (H) and differentiated phenotypes (I) were analyzed by flow cytometry. P values were from unpaired two-tailed Student’s t-tests. *P < 0.05, **P < 0.01, ***P < 0.001.

Fig.8 CD19–CAR T-cells combined with TGF-β inhibitor eliminate B-cell lymphoma. (A) Schematic of experimental design. Briefly, mice were transplanted with Raji–Luc–EGFP cells (1 × 10⁵) on day 7. Mice began to receive combination treatment of TGF-β inhibitor (LY2109761, 50 mg or 100 mg/kg twice daily by oral) on Day −2. On Day 0, mice were treated with PBS, CAR T-cells (1 × 10⁶ cells) or CAR T-cells combined with LY2109761. In the combinatorial groups, LY2109761 (50 or 100 mg/kg twice daily orally, 5 days per week for 8 weeks) was administrated. (B) The tumor burden was measured using bioluminescence imaging. Total bioluminescence was traced in the vehicle, CAR T-cells combined with the LY2109761 group, and CAR T-cells. Error bars represent SEM. (C) Kaplan–Meier analysis of mice survival curve. P values were calculated using unpaired two-tailed Student’s t-tests. *P < 0.05.

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