Immunohistochemical Characterization of Immune Infiltrate in Tumor Microenvironment of Glioblastoma

Abstract

Background: Glioblastoma (GBM) is the most common primary malignant brain cancer in adults, with very limited therapeutic options. It is characterized by a severe immunosuppressive milieu mostly triggered by suppressive CD163+ tumor-associated macrophages (TAMs). The efficacy of immune checkpoint inhibitor interventions aimed at rescuing anti-tumor immunity has not been proved to date. Thus, it is critically important to investigate the immunomodulatory mechanisms acting within the GBM microenvironment for the better design of immunotherapeutic strategies. Methods: The immunohistochemical analysis of a panel of immune biomarkers (CD3, FoxP3, CD163, IDO, PDL-1, PD-1 and TIGIT) was performed in paired samples of the tumor core (TC) and peritumoral area (PTA) of nine GBM patients. Results: CD163+ cells were the most common cell type in both the PTA and TC. IDO and PDL-1 were expressed in most of the TC samples, frequently accompanied by TIGIT expression; on the contrary, they were almost absent in the PTA. CD3+ cells were present in both the TC and PTA, to a lesser extent than CD163+ cells; they often were accompanied by PD-1 expression, especially in the TC. FoxP3 was scarcely present. Conclusion: Distinct inhibitory mechanisms can act simultaneously in both the TC and PTA to contribute to the strong immunosuppression observed within the GBM microenvironment. Nevertheless, the PTA shows strongly reduced immunosuppression when compared to the TC, thus representing a potential target for immunotherapies. Moreover, our results support the working hypothesis that immunosuppression and T-cell exhaustion can be simultaneously targeted to rescue anti-tumor immunity in GBM patients.

Ketogenic Metabolic Therapy, Without Chemo or Radiation, for the Long-Term Management of IDH1-Mutant Glioblastoma: An 80-Month Follow-Up Case Report

“…The glutamine-addicted GBM mesenchymal cells arise from neoplastic microglia/macrophages (118,119). A recent study showed that expression of the macrophage/microglial marker, CD163, was lower in an IDH1mutant GBM than in IDH1 wild-type GBM (120). CD163 is a biomarker for glutamine-dependent neoplastic macrophages in tumor tissue (119,121).…”

Macrophages/Microglia in the Glioblastoma Tumor Microenvironment

“…It is believed that there are different preferential distributions and functions of GAMs in different locations, as well as in different GBM subtypes. In an immunohistochemical analysis of a panel of immune biomarkers within the GBM microenvironment, the CD163 + pro-tumoral macrophages appeared to be the most common cell type in both the peritumoral area (PTA) and the tumor core (TC) [ 14 ]. Similarly, another study proved that in central tumor areas and around vessels in the infiltration zone there were more CD68+ GAMs in slow-growing tumors.…”

Soluble Immune Checkpoints, Gut Metabolites and Performance Status as Parameters of Response to Nivolumab Treatment in NSCLC Patients

“…The clinical benefit of these therapies administrated alone or in combination is already well established in several cancer types (melanoma, lung cancer, renal cell carcinoma) [ 1 , 2 , 3 ]. In other tumors with limited therapeutic options such as glioblastoma, research efforts are focused on possible combination therapies on the tumor microenvironment [ 4 ]. These treatments may confer different benefits if combined with standard therapies [ 5 ].…”