Immunogenic Cell Death Enhances Immunotherapy of Diffuse Intrinsic Pontine Glioma: From Preclinical to Clinical Studies

Abstract

Diffuse intrinsic pontine glioma (DIPG) is the most lethal tumor involving the pediatric central nervous system. The median survival of children that are diagnosed with DIPG is only 9 to 11 months. More than 200 clinical trials have failed to increase the survival outcomes using conventional cytotoxic or myeloablative chemotherapy. Immunotherapy presents exciting therapeutic opportunities against DIPG that is characterized by unique and heterogeneous features. However, the non-inflammatory DIPG microenvironment greatly limits the role of immunotherapy in DIPG. Encouragingly, the induction of immunogenic cell death, accompanied by the release of damage-associated molecular patterns (DAMPs) shows satisfactory efficacy of immune stimulation and antitumor strategies. This review dwells on the dilemma and advances in immunotherapy for DIPG, and the potential efficacy of immunogenic cell death (ICD) in the immunotherapy of DIPG.

Keywords: damage associated molecular patterns; diffuse intrinsic pontine glioma; immune microenvironment; immunogenic cell death; immunotherapy.

Figure 1

MRI images of two patients with radiographically classic DIPG. MRI image of two DIPG cases shows a space-occupying lesion in the pontine region, being relatively hypointense or isointense on T1-weighted images and hyperintense on T2-weighted images, when compared with a normal brain. DIPG Patient 1: 5 years, male; DIPG Patient 2: 7 years, female.

Figure 2

Characterization of the DIPG-associated immune microenvironment. DIPG is a “cold tumor”, indicating reduced immune cells infiltration, lower secretion of inflammatory factors, rare antigen-presenting cells, isolated and defective immune death mechanisms, and a nearly deserted immune microenvironment. Besides, DIPG-associated macrophages do not fully fit the M1 or M2 classification. In general, immunosuppression is not a major feature of the DIPG microenvironment, compared with adult GBM.

Figure 3

Types and dilemmas of immunotherapy for DIPG, and mechanisms by which immunogenic cell death enhances immunotherapy. (A) Cancer immunotherapy is based on the reactivation of anti-tumor immune responses and overcoming immune escape-related pathways. Current treatments utilize ICIs, CAR-T-cells, vaccines, and oncolytic viruses. The use of immunotherapy in DIPG is limited by a non-inflammatory immune microenvironment, lower mutational load, antigen insufficiency, attenuation and escape, toxicity of immunotherapy, blood brain barrier (BBB), and the use of cortisol. (B) ICD inducers can be combined with radiotherapy and immunotherapy for DIPG, resulting in cellular stress and cell death and the concomitant release of damage-associated molecular patterns (DAMPs), i.e., HMBG1, calreticulin, and ATP from dying tumor cells. Recruited dendritic cells assimilate the DIPG tumor antigens that are released from dying cells, such as HMGB1 binding to TLR2/4, which facilitates cytokine production and tumor antigen cross-presentation. The dendritic cells carrying DIPG antigens migrate to the cervical draining lymph node where they present the antigens to naive T-cells, thereby activating anti-DIPG effector T-cells. Primed effector T-cells migrate toward the tumor microenvironment and kill residual DIPG cells.