IDH-mutant gliomas harbor fewer regulatory T cells in humans and mice

Abstract

The metabolic gene isocitrate dehydrogenase 1 (IDH1) is commonly mutated in lower grade glioma (LGG) and secondary glioblastoma (GBM). Regulatory T cells (Tregs) play a significant role in the suppression of antitumor immunity in human glioma. Given the importance of Tregs in the overall framework of designing immune-based therapies, a better understanding on their association with IDH mutational status remains of critical clinical importance. Using multispectral imaging analysis, we compared the incidence of Tregs in IDH-mutant and IDH wild-type glioma from patient tumor samples of LGG. An orthotopic IDH-mutant murine model was generated to evaluate the role of mutant IDH on Treg infiltration by immunohistochemistry. When compared to IDH wild-type controls, Tregs are disproportionally underrepresented in mutant disease, even when taken as a proportion of all infiltrating T cells. Our findings suggest that therapeutic agents targeting Tregs may be more appropriate in modulating the immune response to wild-type disease.

Association of IDH mutation and 1p19q co-deletion with tumor immune microenvironment in lower-grade glioma

“…Recently, IDH mutation status has been reported to be associated with PD-L1 expression and tumor-infiltrating lymphocyte (TIL) infiltration in diffuse gliomas. 23 , 24 , 25 , 26 , 27 Our study was largely in agreement with available data but differed in several important aspects. We integrated IDH mutation and 1p/19q codeletion status and conducted a comprehensive and systematic analysis of 28 immune cell types and their infiltration in these subtypes; the expression of the immune checkpoint components in each subtype was assessed and TMB, MSI, and MHC class I gene expression was categorized in these subtypes.…”

Implications of IDH mutations on immunotherapeutic strategies for malignant glioma

“…15,16 In addition to effector T-cell subsets, our group recently showed a significant reduction in suppressive regulatory T cells (Tregs) in IDH-mutant tumors. 17 In an investigation of a large cohort of diffuse glioma, Berghoff and colleagues showed that the expression of PD-L1, an immunosuppressive cell surface molecule that downregulates T-cell activity, was significantly reduced in IDH-mutant tumors. 16 Recent work by Friebel et al and Mathewson et al further interrogated the transcriptional profiles of tumor-infiltrating T cells and compared their activation states between IDH mutational status.…”

“…15,22 This diminished immune phenotype exhibited by IDH-mutant tumors has been consistently recapitulated in human samples and by other groups studying the immunological consequence of mutant IDH. 16,17,19,20,25 The distinctive immune milieu in IDH-mutant tumors (Fig. 1) may be relevant when developing immune modulating strategies in the future for this molecular class of patients.…”

Dendritic Cell Vaccination of Glioblastoma: Road to Success or Dead End

“…Treg cannot be detected in normal brain, and they are rare in low-grade brain tumors, yet despite lymphopenia, Treg frequencies are increased in the TME as well as in the blood of GBM patients (212)(213)(214)(215). Frequencies may vary by GBM subtype, with the IDH wildtype (Iso-citrate dehydrogenase) and mesenchymal subtypes having higher Treg frequencies than IDH mutated (216) and proneural and classical GBM subtypes, respectively (217). It has been reported that there is an age-dependent increase in the Treg : CD8 + ratio, with a maximal increase in the 60-69 years age group, which coincides with the median age (64 years) of GBM patients at diagnosis (218).…”