Digital expression profile of immune checkpoint genes in medulloblastomas identifies CD24 and CD276 as putative immunotherapy targets

• Published in: Frontiers in immunology Vol. 14; p. 1062856
• Main Authors: Marques, Rui Ferreira, Moreno, Daniel Antunes, da Silva, Luciane, Leal, Leticia Ferro, de Paula, Flávia Escremim, Santana, Iara, Teixeira, Gustavo, Saggioro, Fabiano, Neder, Luciano, Junior, Carlos Almeida, Mançano, Bruna, Reis, Rui Manuel
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 07.02.2023
• Subjects: B7 Antigens; B7-H1 Antigen - genetics; CD24 Antigen; Cerebellar Neoplasms - genetics; Cerebellar Neoplasms - therapy; Child; CTLA-4 Antigen - genetics; Humans; immune checkpoints; immune profile; Immunology; Immunotherapy; medulloblastoma; Medulloblastoma - genetics; Medulloblastoma - therapy; nCounter mRNA expression assay; Programmed Cell Death 1 Receptor - metabolism; RNA, Messenger; immune profile; medulloblastoma; nCounter mRNA expression assay; immunotherapy; immune checkpoints
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2023.1062856

Medulloblastoma is the most common and lethal pediatric malignant brain tumor. It comprises four main molecular subgroups: WNT-activated, SHH-activated, Group 3, and Group 4. Medulloblastoma treatment is surgical resection, craniospinal radiation, and chemotherapy. However, many patients do not respond to therapy, and most suffer severe side effects. Cancer immunotherapy targeting immune checkpoints (IC) (PD-1, PD-L1, and CTLA4) has been getting disappointing outcomes in brain tumors. Nevertheless, other less explored immune checkpoints may be promising candidates for medulloblastoma therapy. In the present study, we aimed to characterize the expression profile of 19 immune checkpoints in medulloblastoma. We analyzed 88 formalin-fixed paraffin-embedded medulloblastomas previously classified for each molecular subgroup and three non-tumoral brain tissue. mRNA levels of 19 immune checkpoint-related genes were quantified using the nCounter (PanCancer Immune Profiling Panel) assay. Further analysis was performed in two larger public microarray datasets, one of which enabled comparisons between tumoral and non-tumoral tissues. Immunohistochemistry of PD-L1 was performed in a subset of cases. Microsatellite instability was also molecularly analyzed. We observed an absence of expression of the canonic ICs, namely (PD-1), (PD-L1), and , as well as , and PD-L1 protein expression was also practically absent. We found higher mRNA levels of , (B7-H3), and , and lower mRNA levels of , , and genes, with significant differences across the four molecular subgroups. Compared to the non-tumor tissues, the expression levels of in all subgroups and in SHH, Group 3, and Group 4 subgroups are significantly higher. The analysis confirmed the expression profile found in the Brazilian cohort, including the lower/absent expression of the canonic ICs. Moreover, it confirmed the overexpression of and in medulloblastomas compared with the non-tumor tissue. Additionally, and CD24 high levels were associated with worse survival. These results highlight the low or absence of mRNA levels of the canonic targetable ICs in medulloblastomas. Importantly, the analysis revealed overexpression of and , which can constitute prognostic biomarkers and attractive immunotherapy targets for medulloblastomas.