Page 82 - Read Online

Sharma et al. Cancer Drug Resist 2023;6:688-708 https://dx.doi.org/10.20517/cdr.2023.82 Page 698

OPPORTUNITIES
Approaches to alter immuno-suppression in glioblastoma TME
Many great efforts have been made to overcome the difficulty of immunotherapy applications in neuro-
oncology. For example, a clinical trial found that neoadjuvant PD-1 blockade resulted in significantly
improved overall survival and progression-free survival in patients with recurrent glioblastoma . In this
[158]
study, patients received anti-PD1 treatment ~2 weeks before surgery, and the PD1 antibody was able to
elicit both systemic and local anti-tumor immunity. Other attempts are primarily focused on modulating
the immune suppression in the glioblastoma tumor microenvironment by targeting various components of
the TME, such as TAMs and MDSCs (summarized in a recent review by Wang et al. ). In the meantime,
[159]
new targets have been identified for future immunotherapy development. For instance, TAMs associated
CD73 was found to be a promising target with potentially synergistic effects along with dual inhibition of
PD1 and CTLA-4 . CD47/SIRPα axis is another exciting target to consider. SIRPα governs the
[160]
phagocytosis activity of MΦ. When CD47 on the cancer cell surface engages with SIRPα on MΦ, it sends a
“Don’t-eat-me” signal to prevent phagocytosis of cancer cells by MΦ. Treatment with anti-CD47 plus TMZ
was shown to activate both innate and adaptive anti-tumor immunity in a preclinical study .
[161]

A single-cell RNA-seq study of patient glioma infiltrating T cells revealed CD161 (KLRB1) as a promising
immunotherapy target. Depleting CD161 led to T cell activation and anti-tumor immunity both in vitro and
in vivo . An independent study using data from a large cohort of glioma patients confirmed that CD161
[162]
might play an important role in promoting glioma progression via inhibition of T cell function .
[163]
Besides checkpoint inhibition, a deeper understanding of the resistance mechanism to CAR-T therapy in
solid tumors was achieved through a genome-wide CRISPR knockout screen in glioblastoma . A recent
[164]
study using a genome-wide CRISPR knockout screen in glioblastoma revealed a functional requirement of
IFN-γ receptor in glioblastoma for sufficient adhesion of CAR-T cells to mediate productive cytotoxicity .
[164]
This study suggests that strategies to enhance the binding of CAR-T cells to the solid tumor will likely result
in a better treatment response. Another strategy to enhance the infiltration of CAR-T cells into glioblastoma
tumors by combining CAR-T with a CXCL11-armed oncolytic virus also demonstrated an improved anti-
tumor immunity in a syngeneic mouse glioma model .
[165]

Combinatorial approaches and new forms of immunotherapies
Combination therapy has been extensively explored to improve glioblastoma treatment. For instance,
resistance to α-VEGF monotherapy was common in glioblastoma. A new study reported that combined
blockade of VEGF, Angiopoietin-2, and PD1 could reprogram glioblastoma endothelial cells into quasi-
antigen-presenting cells and induced a durable anti-tumor T cell response . A recent review has nicely
[166]
summarized the current status of combinatorial approaches, including both chemo- and immunotherapies,
for glioblastoma treatment . Additionally, many new forms of immunotherapy are emerging with great
[167]
hope to shift the paradigm of glioblastoma treatment. A recent study reported a nanoporter (NP)-hydrogel
complex for local induction of CAR-macrophages (CAR-MΦ) targeting CD133+ glioblastoma stem cells in
tumor resection cavity with promising results . This nanomicelle complex consists of a self-assembled
[168]
peptide-based hydrogel loaded with the CD133-targeting CAR construct and then was coated with a
citraconic anhydride–modified dextran with the ability to bind to CD206, a typical surface marker of M2
macrophages. Different from the ex vivo engineering of CAR-MΦ developed by Klichinsky et al. , the
[169]
nanoporter-hydrogel-based in situ induction of strategy CAR-MΦ largely simplified the process of
CAR-MΦ preparation and minimized potential systemic toxicity from CAR-MΦ.