Immune Subtypes and Survival in Patients with Primary Glioma

Gliomas are heterogeneous tumors with poor outcomes following current therapies, including immunotherapy. The tumor microenvironment (TME) is a critical determinant of therapeutic response in gliomas. We have classified the immune TME of gliomas by multiplex immunofluorescence (mIF).

Tissue taken at initial resection from 354 patients with newly-diagnosed glioma grades 2-4 were analyzed using three 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.

Using unsupervised cluster analysis of WHO grade 4 gliomas we identified 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 lymphoid and myeloid immune phenotypes and APCs, 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.

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.