Over the last decade, developments in molecular profiling have radically altered the diagnosis, classification, and management of numerous cancer types, with primary brain tumors being no exception. Although historically brain tumors have been classified based on their morphological characteristics, recent advances have allowed refinement of tumor classification based on molecular alterations. This shift toward molecular classification of primary brain tumors is reflected in the 2021 5th edition of the WHO classification of central nervous system tumors (WHO 2021). In this review, we will discuss the most recent updates to the classification of adult‐type diffuse gliomas, a group of highly infiltrative and largely incurable CNS malignancies. It is our hope continued that refinement of molecular criteria will improve diagnosis, prognostication, and eventually treatment of these devastating tumors.
Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations inATRX, defining molecular alterations inIDH-mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss andIDHmutation on innate immunity. To explore this, we generatedATRXknockout glioma models in the presence and absence of theIDH1R132Hmutation. ATRX-deficient glioma cells were sensitive to dsRNA-based innate immune agonism and exhibited impaired lethality and increased T-cell infiltration in vivo. However, the presence ofIDH1R132Hdampened baseline expression of key innate immune genes and cytokines in a manner restored by genetic and pharmacological IDH1R132Hinhibition. IDH1R132Hco-expression did not interfere with theATRXKO-mediated sensitivity to dsRNA. Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1R132H reversibly masks this priming. This work reveals innate immunity as a therapeutic vulnerability of astrocytoma.
ATRX is a key chromatin regulator, which is mutated in large subsets of both adult and pediatric gliomas. Despite being a common mutation, little is known about the biological ramifications of ATRX deficiency. Recently, it has been demonstrated that ATRX deficiency drives increased replication stress, DNA damage, and global epigenetic dysregulation. Despite these advances, little is known about the impact of ATRX deficiency on the tumor microenvironment (TME). In order to explore the impact of ATRX deficiency on the TME we utilized the RCAS/nTVa system to generate a novel murine model of ATRX deficient glioma. Mice bearing allografts of these tumors displayed significantly increased survival relative to the ATRX intact lines. This survival benefit persisted in Nu/nu mice, which lack an adaptive immune system, but not in SCID mice, which lack both adaptive and innate immunity. Bulk RNA sequencing revealed the ATRX deficient tumors displayed increased expression of inflammatory and innate immune gene sets, and western blotting revealed increased phosphorylation of tank binding kinase 1 (TBK1), a key innate immune regulator. Multiplex cytokine analysis of conditioned media also revealed increased expression of inflammatory cytokines such as CCL2, CCL5, and CXCL10 in the supernatant of ATRX deficient cell lines. Taken together, these results indicate that ATRX deficiency can drive innate immune activation, and that this activation can increase survival in vivo. Further exploration is needed to characterize the upstream drivers of TBK1 activation and elucidate alterations to immune cell infiltration in ATRXdeficient tumors.
Harnessing the immune system through the attenuation of endogenous immune checkpoints on T-cells has led to dramatic, durable tumor rejection in multiple solid tumors; however, most cancer types remain resistant to immunotherapy. It is imperative to understand the unique mechanisms by which these lethal malignancies evade the immune system in order to design efficacious therapies. Research by several groups is elucidating how overall mutational burden, tumor stroma, and patient microbiome predict response to immunotherapies in immune-resistant cancers. However, the frequency and distribution of driver mutations in the tumors themselves differ between immunogenic and non-immunogenic cancer types and may play a role in immune escape. Whereas p53, the most commonly mutated gene in cancer, is mutated in 70-90% of non-immunogenic tumors like pancreatic adenocarcinoma (PDAC), it is mutated in only 10-15% of immunogenic skin cutaneous melanoma cases. Loss of p53 through truncating mutations mediates tumor escape from apoptosis and senescence. Furthermore, many p53 missense mutations (mtp53) not only lose wild-type activity (LOF), but acquire novel gain-of-function (GOF) activities which promote oncogenesis and resistance to therapy. Pre-clinical data suggest that mtp53 differentially mediates tumor escape from immune surveillance by altering the innate immune response, including NK cell function and macrophage phenotype, thereby allowing tumorigenesis through chronic local immunosuppression. Few studies have been completed, however, to demonstrate the role of mtp53 in regulating the adaptive immune response. Understanding the role of p53 and its mutants in the regulation of T-cell function in cancer would provide a novel framework by which to understand and overcome resistance to cancer immunotherapy in many deadly cancer types. We hypothesize that mtp53 mediates evasion of T-cell anti-tumor activity, and that gain-of-function pathways downstream of mtp53 drive this process. Here we elaborate on previously presented work, elucidating how GOF vs. LOF mtp53 influences T-cell infiltration and killing using both novel model systems. Ultimately, these results may define a new role for mtp53 in influencing the immune system, and provide a rationale for developing effective combination strategies to improve response to immunotherapy. Citation Format: Deborah A. Silverman, Emily Ashkin, Benjamin Whitfield, Simone Punt, Soraya Zorro Manrique, Yunfei Wang, Anil Korkut, Leila Williams, Minying Zhang, Eran Kotler, Moshe Oren, Anirban Maitra, Patrick Hwu. Tumoral p53 mutations differentially mediate poor T-cell infiltration and autologous T-cell killing in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2372.
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