CXCL14 Promotes a Robust Brain Tumor-Associated Immune Response in Glioma

  • Kumar A
  • Mohamed E
  • Tong S
  • et al.
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Abstract

Purpose: The immunosuppressive tumor microenvironment present in the majority of diffuse glioma limits therapeutic response to immunotherapy. As the determinants of the glioma-associated immune response are relatively poorly understood, the study of glioma with more robust tumor-associated immune responses may be particularly useful to identify novel immunomodulatory factors that can promote T cell effector function in glioma. Experimental Design: We used multiplex immune-profiling, proteomic profiling, and gene expression analysis to define the tumor-associated immune response in two molecular subtypes of glioma and identify factors that may modulate this response. We then used patient-derived glioma cultures and an immunocompetent murine model for malignant glioma to analyze the ability of tumor-intrinsic factors to promote a CD8+ T cell response. Results: As compared with IDH-mutant astrocytoma, MAPK-activated pleomorphic xanthoastrocytoma (PXA) harbored increased numbers of activated cytotoxic CD8+ T cells and Iba1+ microglia/macrophages, increased MHC class I expression, enrichment of genes associated with antigen presentation and processing, and increased tumor cell secretion of the chemokine CXCL14. CXCL14 promoted activated CD8+ T cell chemotaxis in vitro, recruited tumor-infiltrating CD8+ T cells in vivo, and prolonged overall survival in a cytotoxic T cell-dependent manner. The immunomodulatory molecule B7-H3 was also highly expressed in PXA. Conclusions: We identify the MAPK-activated lower grade astrocytoma PXA, as having an immune-rich tumor microenvironment and suggest this tumor may be particularly vulnerable to immunotherapeutic modulation. We also identify CXCL14 as an important determinant of the glioma-associated immune microenvironment, sufficient to promote an anti-tumor CD8+ T cell response.

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Kumar, A., Mohamed, E., Tong, S., Chen, K., Mukherjee, J., Lim, Y., … Phillips, J. J. (2022). CXCL14 Promotes a Robust Brain Tumor-Associated Immune Response in Glioma. Clinical Cancer Research, OF1–OF13. https://doi.org/10.1158/1078-0432.ccr-21-2830

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