Brain tumors induce immunoregulatory dendritic cells in draining lymph nodes that can be targeted by OX40 agonist treatment.

in Journal for immunotherapy of cancer by Oscar Badillo-Godinez, Jenni Niemi, Liam Helfridsson, Shokoufeh Karimi, Mohanraj Ramachandran, Hitesh Bhagavanbhai Mangukiya, Sven Nelander, Mats Hellström

TLDR

  • The study reveals that cervical dendritic cells (DC-c) play a unique role in regulating the immune response in the central nervous system (CNS) and suggests the importance of OX40 signaling in antitumor immunity.
  • The findings have implications for the development of therapies targeting OX40 signaling in DC-c to enhance antitumor immunity in CNS tumors.

Abstract

Primary and metastatic brain tumors have a poor prognosis, partly owing to the unique characteristics of the central nervous system (CNS) and tumor immune microenvironment (TIME). One distinct feature of the CNS TIME is the limited infiltration and activation of dendritic cells (DCs). The impact of CNS versus non-CNS TIME can be assessed by injecting tumor cells from the same model, either subcutaneously (peripherally) or into the brain. Subcutaneous tumors drain into the tumor-draining lymph nodes in the skin (TdLN-p), whereas brain tumors drain into the deep cervical TdLN (TdLN-c). We previously showed that CNS tumors that are not responsive to immune checkpoint inhibition become responsive when grown peripherally, and that non-responsiveness correlates with a tolerogenic immune response in the local TIME and TdLN-c. In this study, we investigated the immunoregulatory potential of cervical DCs (DC-c) compared with that of peripheral DCs (DC-p) using high-resolution flow cytometry, single-cell RNA sequencing, and ex vivo and in vivo functional characterization of TdLNs from mouse models of glioma and lymphoma. Our analysis revealed that DC-c promoted regulatory T-cell expansion and poorly cytotoxic CD8T cells compared with DC-p. Furthermore, we identified OX40 () as a modulator of immunoregulatory DC-c function and found that its antitumor effect depended on lymphocyte trafficking and the DC transcription factor. CCR7+OX40+ DCs were efficient in antigen processing and presentation, and OX40 agonists further enhanced DC activation. In TIME, the CCR7+OX40+ DCs expressed OX40L, and blocking it promoted Treg formation ex vivo. Our findings highlight the unique immunoregulatory functions of DC-c in TdLNs and suggest the importance of OX40 signaling through direct effects on CCR7+OX40+ DCs and indirect effects on T cells.

Overview

  • The study investigates the immunoregulatory potential of cervical dendritic cells (DC-c) compared to peripheral DCs (DC-p) in mouse models of glioma and lymphoma.
  • The researchers used high-resolution flow cytometry, single-cell RNA sequencing, and ex vivo and in vivo functional characterization of tumor-draining lymph nodes (TdLNs) to analyze DC-c and DC-p.
  • The primary objective of the study is to understand the role of DC-c and OX40 signaling in regulating immune responses in the central nervous system (CNS) and its impact on tumor growth.

Comparative Analysis & Findings

  • The study found that DC-c promote regulatory T-cell expansion and poorly cytotoxic CD8T cells compared to DC-p.
  • The researchers identified OX40 as a modulator of immunoregulatory DC-c function and found that its antitumor effect depended on lymphocyte trafficking and the DC transcription factor.
  • CCR7+OX40+ DCs were efficient in antigen processing and presentation, and OX40 agonists further enhanced DC activation.

Implications and Future Directions

  • The study highlights the unique immunoregulatory functions of DC-c in TdLNs and suggests the importance of OX40 signaling through direct effects on CCR7+OX40+ DCs and indirect effects on T cells.
  • Future studies could investigate the therapeutic potential of targeting OX40 signaling in DC-c to enhance antitumor immunity in CNS tumors.
  • The study emphasizes the need for further research on the distinct immunoregulatory mechanisms in the CNS TIME to develop effective therapies for brain tumors.
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