Immune subtypes and survival in patients with primary glioma.

Abstract

Background: The tumor microenvironment (TME) is a critical determinant of glioma response to therapies, including immunotherapy. We have classified the immune TME of gliomas by multiplex immunofluorescence (mIF).

Methods: Tissue taken at initial resection from 354 patients with newly diagnosed glioma grades 2-4 were analyzed using 3 mIF panels of markers for T, B, and myeloid cells. Tumor cores were characterized by the relative abundances of: (i) 15 primary immune phenotypes, (ii) 96 secondary immune phenotypes, and (iii) 29 biologically meaningful multi-marker immune phenotypes.

Results: Unsupervised cluster analysis of WHO grade 4 diffuse gliomas revealed four subtypes α, β, γ, and δ that were internally reproducible. Immune subtype α was characterized by high abundance of antigen-presenting cells (APCs) and low levels of MHC II^- monocytes. Subtype β was high in regulatory T cells and myeloid cells, but low in lymphocytes with effector functions. Subtype γ displayed high abundance of immune cell phenotypes, particularly lymphocytes with effector or helper functions. Subtype δ was low in immune phenotypes, with poorer outcomes. Grade 3 tumors could also be classified into α, β, γ, and δ subtypes, indicating generalizability of these immune TME subtypes across high-grade gliomas. Additionally, grade 2 tumors could be classified into subtypes ε, ρ and τ identified in grade 3 tumors.

Conclusions: We have identified internally reproducible criteria for classifying gliomas according to the immune microenvironment, findings that could aid our understanding of the natural progression of low- and high-grade gliomas and inform the rational application of immune-oncologic therapeutic interventions.