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ileged site, regulatory immune cells and cytokines protect against excessive inflammation that would cause
[14]
unacceptable inflammation involving the brain . As brain tumors expand, local tissue damage and hypoxia
induce regulatory cytokines and immune cells to quell inflammation and promote healing [15,16] . These fac-
tors contribute to the immunosuppressive behavior of the tumor itself and can blunt an anti-tumor immune
response.

A typical endogenous immune response occurs in two phases. Pathogens, damaged DNA, cellular debris
from apoptosis or necrosis, and inflammatory cytokines attract phagocytes, natural killer cells, and antigen-
presenting cells as part of the innate immune response. Antigen-presenting cells then display peptide epit-
opes on MHC molecules, which engage T cells through their T cell receptor as part of the adaptive immune
response.

Cells employ sophisticated DNA maintenance machinery to monitor and repair the genome, and damage-
[17]
sensing pathways are important for eliminating pre-cancerous and cancerous cells . Conventional che-
motherapy and radiation, as well as innate-based immunotherapies, induce DNA damage and cell death
by either apoptosis or non-apoptotic pathways [14,18,19] . Cell death and DNA degradation produce molecules
called damage-associated molecular patterns (DAMP), which are recognized by the innate immune system
and promote an immune response. DNA damage-sensing machinery within the nucleus transmits this sig-
nal to the cytoplasm and activates stimulator of interferon genes (STING) to induce proinflammatory inter-
feron signals, which can shift the immunosuppressive tumor bed toward a more inflammatory, anti-tumor
[17]
state . DNA damage sensors also induce cell-surface ligand expression to recruit natural kill cells, natural
killer T cells, and phagocytes to eliminate damaged cells and prime an adaptive immune response against the
tumor [20,21] .

In health, damage-sensing pathways preserve the integrity of the genome and recruit the immune system to
eliminate damaged cells when needed. In many instances, tumors deactivate the cellular damage-sensing
machinery, which allows immune evasion and can dampen the response to conventional therapies like ra-
[22]
diation or immunotherapies that are directly cytotoxic . In addition, mutations within the damage-sensing
[22]
machinery itself can contribute to tumorigenesis . In this way, tumors with high mutational loads are more
likely to harbor deleterious mutations within damage-sensing genes. This explains, in part, why hypermu-
[23]
tated tumors are often resistant to radiation and alkylating chemotherapy .

Defective damage response pathways have implications for immunotherapy as well. Innate-based immu-
notherapies are typically inflammatory and attempt to kill target cells to increase tumor antigen exposure.
Tumor cells that lack damage-sensing machinery and have defective death pathways will be less amenable
to many innate-based immune responses. The ultimate goal of any immunotherapy is to create a T cell re-
sponse targeting the entire tumor and generates immunologic memory to protect against recurrence. With
this understanding how mutational load, tumor neoantigens, and DNA damage machinery affect tumor
immunology, we will discuss approaches in each of the main areas of immunotherapy for pediatric brain
tumors.

VIROTHERAPY
Virotherapy broadly refers to the use of viruses as therapeutic agents. Oncolytic viruses, which cause tumor
cell death and can stimulate the immune system, are the most prominent clinical branch of virotherapy.
Viruses are also useful as vectors for gene therapy, whereby viruses induce expression of a transgene that
modifies the immune environment to promote an anti-tumor response. Retroviruses are used to genetically
modify immune cells, most notably to express chimeric antigen receptors (CAR) on primary human T cells,
and this will be discussed subsequently under adoptive cellular therapy. The last clinical branch of virother-
apy, termed viral immunotherapy, uses viruses to introduce antigens that sensitize the host immune system