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Single cell sequencing reveals that CD39 inhibition mediates changes to the tumor microenvironment.

ABSTRACT: Single-cell sequencing technologies have noteworthily improved our understanding of the genetic map and molecular characteristics of bladder cancer (BC). Here we identify CD39 as a potential therapeutic target for BC via single-cell transcriptome analysis. In a subcutaneous tumor model and orthotopic bladder cancer model, inhibition of CD39 (CD39i) by sodium polyoxotungstate is able to limit the growth of BC and improve the overall survival of tumor-bearing mice. Via single cell RNA sequencing, we find that CD39i increase the intratumor NK cells, conventional type 1 dendritic cells (cDC1) and CD8 + T cells and decrease the Treg abundance. The antitumor effect and reprogramming of the tumor microenvironment are blockaded in both the NK cells depletion model and the cDC1-deficient Batf3^-/- model. In addition, a significant synergistic effect is observed between CD39i and cisplatin, but the CD39i + anti-PD-L1 (or anti-PD1) strategy does not show any synergistic effects in the BC model. Our results confirm that CD39 is a potential target for the immune therapy of BC.

SUBMITTER: Liu L

PROVIDER: S-EPMC9643495 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Single cell sequencing reveals that CD39 inhibition mediates changes to the tumor microenvironment.

Liu Lilong L Hou Yaxin Y Deng Changqi C Tao Zhen Z Chen Zhaohui Z Hu Junyi J Chen Ke K

Nature communications 20221108 1

Single-cell sequencing technologies have noteworthily improved our understanding of the genetic map and molecular characteristics of bladder cancer (BC). Here we identify CD39 as a potential therapeutic target for BC via single-cell transcriptome analysis. In a subcutaneous tumor model and orthotopic bladder cancer model, inhibition of CD39 (CD39i) by sodium polyoxotungstate is able to limit the growth of BC and improve the overall survival of tumor-bearing mice. Via single cell RNA sequencing, ...[more]

PMID: 36347860

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Project description:ObjectivesIn recent years, immune checkpoint inhibitors have shown promise as neoadjuvant therapies in the treatment of locally advanced oral squamous cell carcinoma (OSCC). However, the factors affecting the tumor response to immune checkpoint inhibitors (ICIs) remain unclear. This study aimed to analyze the impact of neoadjuvant chemoimmunotherapy (NACI) on the tumor microenvironment of OSCC via single-cell RNA sequencing, with the goal of optimizing treatment strategies.MethodsWe analyzed biopsy, primary tumor, matched metastatic lymph node, and normal lymph node samples from four patients with OSCC receiving two cycles of tislelizumab (200 mg), albumin-bound paclitaxel (260 mg/m2), and cisplatin (60-75 mg/m2), with 3-week intervals between each cycle. This study explored the tumor microenvironment characteristics of tumors and metastatic lymph nodes in response to NACI.ResultsWe identified two major tumor cell subpopulations (C9 and C11), and patients with high expression of C11 subgroup-specific genes had a lower survival rate. FOXP3+ CD4 eTreg cells were found to potentially suppress the immune response. We found that NACI enhances antitumor immunity by promoting the proliferation of granzyme-expressing CD8+ T effector cells while simultaneously diminishing the effect of CD4+ T cells on Treg-mediated immune suppression. Furthermore, NACI was effective in suppressing inflammatory processes mediated by myeloid cells in tumors, contributing to its antitumor effects. The CCL19+ fibroblastic reticular cell (FRC) subgroup was significantly associated with the efficacy of NACI in patients with OSCC. We found that CCL19+ FRCs primarily exert their antitumor effects through interactions with CD8+ T lymphocytes via the -CXCL12‒CXCR4 axis.ConclusionWe explored the immune landscape of primary OSCC tumors and metastatic lymph nodes in relation to clinical response to NACI. Our findings offer valuable insights into patient treatment responses and highlight potential new therapeutic targets for the future management of OSCC.

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Single cell sequencing reveals that CD39 inhibition mediates changes to the tumor microenvironment.

Publications

Single cell sequencing reveals that CD39 inhibition mediates changes to the tumor microenvironment.

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