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

Clinical cancer research : an official journal of the American Association for Cancer Research 2022 Jul 01

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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. 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. As compared with isocitrate dehydrogenase (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. 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 antitumor CD8+ T-cell response. ©2022 American Association for Cancer Research.

Citation

Anupam Kumar, Esraa Mohamed, Schuyler Tong, Katharine Chen, Joydeep Mukherjee, Yunita Lim, Cynthia M Wong, Zoe Boosalis, Anny Shai, Russell O Pieper, Nalin Gupta, Arie Perry, Andrew W Bollen, Annette M Molinaro, David A Solomon, Joseph T C Shieh, Joanna J Phillips. CXCL14 Promotes a Robust Brain Tumor-Associated Immune Response in Glioma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2022 Jul 01;28(13):2898-2910