Immune Microenvironment and Immunotherapies for Diffuse Intrinsic Pontine Glioma

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a primary glial glioma that occurs in all age groups but predominates in children and is the main cause of solid tumor-related childhood mortality. Due to its rapid progression, the inability to operate and insensitivity to most chemotherapies, there is a lack of effective treatment methods in clinical practice for DIPG patients. The prognosis of DIPG patients is extremely poor, with a median survival time of no more than 12 months. In recent years, there have been continuous breakthroughs for immunotherapies in various hematological tumors and malignant solid tumors with extremely poor prognoses, which provides new insights into tumors without effective treatment strategies. Meanwhile, with the gradual development of stereotactic biopsy techniques, it is gradually becoming easier and safer to obtain live DIPG tissue, and the understanding of the immune properties of DIPG has also increased. On this basis, a series of immunotherapy studies of DIPG are under way, some of which have shown encouraging results. Herein, we review the current understanding of the immune characteristics of DIPG and critically reveal the limitations of current immune research, as well as the opportunities and challenges for immunological therapies in DIPG, hoping to clarify the development of novel immunotherapies for DIPG treatment.

Keywords: diffuse intrinsic pontine glioma; immune checkpoint inhibitor; immune microenvironment; immunotherapy; oncolytic virus; vaccine.

Figure 1

The epigenetic and immune microenvironment characteristics of DIPG. Most DIPGs have hypomethylation of H3K27. Compared with other high-grade gliomas, DIPG has lower CD3⁺T cell infiltration and a higher proportion of CD11b⁺ cell infiltration in its immune microenvironment. There is little expression of inhibitory immune checkpoints in DIPG, the expression of immunosuppressive cytokines is relatively low and the expression of proinflammatory factors is relatively high compared with high grade glioma.

Figure 2

Immunotherapy strategies for DIPG. CAR T cells and TCR T cells are designed to target DIPG cells. Oncolytic viruses are designed to infect DIPG cells, kill them directly or attenuate their progression. A vaccine is injected to activate the adaptive immune system, especially CD8+ cytotoxic T cells. Anti-PD-1 and anti-CTLA-4 antibodies bind to PD-1 and CTLA-4, impeding the inactivation of CD8+ T cells, respectively. ¹³¹I-omburtamab can kill DIPG cells by targeting B7-H3 and internal irradiation. CAR T, chimeric antigen receptor T cells; TCR T, T-cell receptor-gene engineered T cells; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed cell death protein 1; DC, dendritic cell.