Page 202 - Read Online

Page 2 of 16 Landi et al. Neuroimmunol Neuroinflammation 2018;5:29 I http://dx.doi.org/10.20517/2347-8659.2018.35

their disease have significant cognitive disability that limits their ability to live independently, progress fully
[4]
in their education, or pursue a vocation .

Immunotherapy attempts to leverage the high specificity of the immune system to target and eliminate can-
cer cells while leaving healthy cells undamaged. Chimeric antigen receptor (CAR) T cells and PD-1/PD-L1
monoclonal antibodies are the most impactful immunotherapies to date and have cured patients who oth-
erwise had no curative option. Unfortunately, these successes have not significantly improved outcomes for
most children with brain tumors. Understanding the immune environment in which pediatric brain tumors
exist is requisite for identifying effective immune-based therapies for these diseases.

Historically, the blood-brain barrier and perceived sensitivity of deep midline structures to manipulation
have limited investigators’ ability to develop and deliver therapies for children with brain tumors. In the
modern era, direct delivery methods, improved drug design, and surgical intervention involving brainstem
and deep midline tumors drive the field forward. This review will indicate the routes whereby immuno-
therapies are delivered and mechanisms through which they selectively target the tumor, but will not unduly
focus on the blood-brain barrier or tumor delivery methods.

IMMUNOLOGICALLY “HOT” VS. “COLD” TUMORS AND MUTATIONAL LOAD
“Hot” vs. “cold” tumors are distinguished by whether significant numbers of tumor infiltrating lymphocytes
[5]
(TILs), most notably T cells, are present . Functionally, T cells are potently cytolytic and are important
[6]
for immunologic memory and surveillance to maintain an anti-tumor immune response . T cell homing
is influenced by activating cytokines, the tumor vasculature, integrins, and the presence of tumor-specific
[5]
proteins, called “neoantigens” . Hot tumors supply inflammatory cytokines and allow T cells permissive
access within the tumor bed. Cold tumors lack T cell infiltration either because of a harshly immunosup-
pressive tumor microenvironment, or because the tumor is not inflammatory or exists in a strictly immune-
privileged site. Whereas the central nervous system (CNS) was formerly regarded as immune-privileged,
this notion has been dispelled; immune cells are highly adept at reaching the CNS, even without blood brain
[7]
barrier disruption .

In addition to inflammatory cytokines and permissive vasculature, hot tumors tend to exhibit a high num-
ber of neoantigens, which are novel peptide epitopes caused by mutations in the cancer genome. Non-syn-
onymous mutations are changes in the cancer genome that produce an altered amino acid sequence that can
[8]
drive tumorigenesis by altering cellular pathways or lead to expression of neoantigens . Synonymous muta-
tions do not change the amino acid sequence of an expressed gene but are not necessarily silent mutations.
Synonymous mutations can serve as driver mutations by influencing translation, transcription, splicing, and
[9]
mRNA transport .
Melanoma and lung cancer are hot tumors that sometimes respond to immune checkpoint blockade [10,11] .
Ultraviolet light in melanoma and smoke carcinogens in lung cancer induce DNA damage, and these tumors
[8]
in older adults have accumulated higher numbers of non-synonymous mutations . Pediatric cancers harbor
few somatic mutations compared to adult tumors, and this is particularly true for pediatric brain tumors,
which are almost always immunologically cold [12,13] . The lower tumor mutational load in pediatric brain
tumors produces few neoantigens to stimulate T cell activation and proliferation within the tumor bed. Ac-
cordingly, an immunotherapy aimed at promoting an existing T cell immune response, such as checkpoint
blockade, will be ineffective.

DAMAGE RESPONSE AND TUMOR IMMUNITY
Inflammation is an important component of an immune response. While the CNS is not an immune-priv-