Strategies to overcome low MHC-I expression in paediatric and adult tumours

Immunotherapy has made significant advancements in cancer treatments, improving patients' survival rates and quality of life. Several challenges still need to be addressed, which include the considerable fraction of incomplete curative responses in cancer patients, the development of therapy resistance by tumours, and the occurrence of adverse effects, such as inflammatory and autoimmune complications. Paediatric tumours usually exhibit lower responsiveness to immunotherapies compared to adult tumours. Although the underlying reasons are not yet fully understood, one known mechanism by which tumours avoid immune recognition is through reduced cell surface expression of major histocompatibility complex class I (MHC-I) complexes. Accordingly, the reduced presentation of neoantigens by MHC-I hinders the recognition and targeting of tumour cells by CD8+ T cells, impeding T-cell-mediated cytotoxic anti-tumour responses. MHC-I downregulation indeed often correlates with a poorer prognosis and diminished response to immunotherapy. Understanding the mechanisms underlying MHC-I downregulation in different types of paediatric and adult tumours is crucial for developing strategies to restore MHC-I expression and enhance anti-tumour immune responses. We here discuss progress in MHC-I-based immunotherapies against cancers

A multidimensional analysis reveals distinct immune phenotypes and the composition of immune aggregates in pediatric acute myeloid leukemia

\ua9 The Author(s) 2024.Because of the low mutational burden and consequently, fewer potential neoantigens, children with acute myeloid leukemia (AML) are thought to have a T cell-depleted or ‘cold’ tumor microenvironment and may have a low likelihood of response to T cell-directed immunotherapies. Understanding the composition, phenotype, and spatial organization of T cells and other microenvironmental populations in the pediatric AML bone marrow (BM) is essential for informing future immunotherapeutic trials about targetable immune-evasion mechanisms specific to pediatric AML. Here, we conducted a multidimensional analysis of the tumor immune microenvironment in pediatric AML and non-leukemic controls. We demonstrated that nearly one-third of pediatric AML cases has an immune-infiltrated BM, which is characterized by a decreased ratio of M2- to M1-like macrophages. Furthermore, we detected the presence of large T cell networks, both with and without colocalizing B cells, in the BM and dissected the cellular composition of T- and B cell-rich aggregates using spatial transcriptomics. These analyses revealed that these aggregates are hotspots of CD8+ T cells, memory B cells, plasma cells and/or plasmablasts, and M1-like macrophages. Collectively, our study provides a multidimensional characterization of the BM immune microenvironment in pediatric AML and indicates starting points for further investigations into immunomodulatory mechanisms in this devastating disease

Strategies to overcome low MHC-I expression in paediatric and adult tumours

Immunotherapy has made significant advancements in cancer treatments, improving patients’ survival rates and quality of life. Several challenges still need to be addressed, which include the considerable fraction of incomplete curative responses in cancer patients, the development of therapy resistance by tumours, and the occurrence of adverse effects, such as inflammatory and autoimmune complications. Paediatric tumours usually exhibit lower responsiveness to immunotherapies compared to adult tumours. Although the underlying reasons are not yet fully understood, one known mechanism by which tumours avoid immune recognition is through reduced cell surface expression of major histocompatibility complex class I (MHC-I) complexes. Accordingly, the reduced presentation of neoantigens by MHC-I hinders the recognition and targeting of tumour cells by CD8+ T cells, impeding T-cell-mediated cytotoxic anti-tumour responses. MHC-I downregulation indeed often correlates with a poorer prognosis and diminished response to immunotherapy. Understanding the mechanisms underlying MHC-I downregulation in different types of paediatric and adult tumours is crucial for developing strategies to restore MHC-I expression and enhance anti-tumour immune responses. We here discuss progress in MHC-I-based immunotherapies against cancers.</p