Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy

Hodges, Tiffany R.; Ott, Martina; Xiu, Joanne; Gatalica, Zoran; Swensen, Jeff; Zhou, Shouhao; Huse, Jason T.; Groot, John de; Li, Shulin; Overwijk, Willem W.; Spetzler, David; Heimberger, Amy B.

doi:10.1093/neuonc/nox026

Cited by 353 publications

(315 citation statements)

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“…Further studies will be needed to determine whether therapeutic drug combinations to manipulate these factors will, in turn, directly impact intratumoral immune cytolytic activity and lead to an immune-mediated anti-tumor effect. Consistent with other studies [7,27,35], we found no association between the non-synonymous TMB and the degree of intratumoral immune cytolytic activity in GBM.…”

Section: Discussionsupporting

confidence: 92%

“…However, despite promise in preclinical and early phase studies [2,3], single agent programmed death 1 (PD-1) inhibition is ineffective for recurrent GBM in the absence of a rare, markedly hypermutated tumor [4–6]. This is due, in part, to the relative paucity of intratumoral T cells in GBM compared to cancers with carcinogen-induced mutational signatures and high tumor mutational burden (TMB) [7–11]. Even in GBMs with higher than average TMB, there does not appear to be a resultant influx of CD8+ T cells or increase in PD-1/PD-L1 expression [7].…”

Section: Introductionmentioning

confidence: 99%

“…This is due, in part, to the relative paucity of intratumoral T cells in GBM compared to cancers with carcinogen-induced mutational signatures and high tumor mutational burden (TMB) [7–11]. Even in GBMs with higher than average TMB, there does not appear to be a resultant influx of CD8+ T cells or increase in PD-1/PD-L1 expression [7]. Furthermore, approaches for increasing intratumoral T cells in GBM, such as vaccines, oncolytic viruses, or chimeric antigen receptor (CAR) T cells, are hindered by a severely immunosuppressive tumor microenvironment [12–14].…”

Section: Introductionmentioning

confidence: 99%

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RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma

et al. 2018

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Introduction: We sought to determine which therapeutically targetable immune checkpoints, costimulatory signals, and other tumor microenvironment (TME) factors are independently associated with immune cytolytic activity (CYT), a gene expression signature of activated effector T cells, in human glioblastoma (GBM). Methods: GlioVis was accessed for RNA-seq data from The Cancer Genome Atlas (TCGA). For subjects with treatment-naïve, primary GBM, we quantified mRNA expression of 28 therapeutically targetable TME factors. CYT (geometric mean of GZMA and PRF1 expression) was calculated for each tumor. Multiple linear regression was performed to determine the relationship between the dependent variable (CYT) and mRNA expression of each of the 28 factors. Variables associated with CYT in multivariate analysis were subsequently evaluated for this association in an independent cohort of newly diagnosed GBMs from the Chinese Glioma Cooperative Group (CGCG). Results: 109 TCGA tumors were analyzed. The final multiple linear regression model included the following variables, each positively associated with CYT except VEGF-A (negative association): CSF-1 (p=0.003), CD137 (p=0.042), VEGF-A (p<0.001), CTLA4 (p=0.028), CD40 (p=0.023), GITR (p=0.020), IL6 (p=0.02), and OX40 (p<0.001). In CGCG (n=52), each of these variables remained significantly associated with CYT in univariate analysis except for VEGF-A. In multivariate analysis, only CTLA4 and CD40 remained statistically significant. Conclusions: Using multivariate modeling of RNA-seq gene expression data, we identified therapeutically targetable TME factors that are independently associated with intratumoral cytolytic T-cell activity in human GBM. As a myriad of systemic immunotherapies are now available for investigation, our results could inform rational combinations for evaluation in GBM.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma

et al. 2018

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“…Balachandran et al 2017; Brown et al 2014; Gros et al 2016; Hodges et al 2017; Lauss et al 2017; Linnemann et al 2015; Luksza et al 2017; Matsushita et al 2012; McGranahan et al 2016; Ock et al 2017; Pritchard et al 2015a; Rizvi et al 2015; Robbins et al 2013; Snyder et al 2014; Tran et al 2016; Van Allen et al 2015; van Rooij et al 2013; Verdegaal et al 2016). While these various tools have an important role to play in the prediction of immunogenic antigens, the majority of the identified epitopes do not initiate an immune response (e.g.…”

Section: Identification Of Neoantigensmentioning

confidence: 99%

Identifying neoantigens for use in immunotherapy

Hutchison

Pritchard

2018

Mamm Genome

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This review focuses on the types of cancer antigens that can be recognised by the immune system and form due to alterations in the cancer genome, including cancer testis, overexpressed and neoantigens. Specifically, neoantigens can form when cancer cell-specific mutations occur that result in alterations of the protein from 'self'. This type of antigen can result in an immune response sufficient to clear tumour cells when activated. Furthermore, studies have reported that the likelihood of successful immunotherapeutic targeting of cancer by many different methods was reliant on immune response to neoantigens. The recent resurgence of interest in the immune response to tumour cells, in conjunction with technological advances, has resulted in a large increase in the predicted, identified and functionally confirmed neoantigens. This growth in identified neoantigen sequences has increased the contents of training sets for algorithms, which in turn improves the prediction of which genetic mutations may form neoantigens. Additionally, algorithms predicting how proteins will be processed into peptide epitopes by the proteasome and which peptides bind to the transporter complex are also improving with this research. Now that large screens of all the tumour-specific protein altering mutations are possible, the emerging data from assessment of the immunogenicity of neoantigens suggest that only a minority of variants will form targetable epitopes. The potential for immunotherapeutic targeting of neoantigens will therefore be greater in cancers with a higher frequency of protein altering somatic variants. There is considerable potential in the use of neoantigens to treat patients, either alone or in combination with other immunotherapies and with continued advancements, these potentials will be realised.

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“…Mildenberger et al (pp. 650-658) point out the limitations of checkpoint inhibitions in GBM in which several factors, including relatively low mutational load and neoepitopes, constitute negative predictive factor of response [11]. The situation could be different in recurrent low-grade gliomas, because the relatively slow growth of the tumor allows the accumulation of mutations, particularly in some patients pretreated with Temozolomide (hypermutator phenotype) and could also give enough time for an endogenous T-cell response to become effective.…”

Section: Improving Diagnosis and Management Of Primary Brain Tumorsmentioning

confidence: 99%

Improving diagnosis and management of primary brain tumors

Delattre

2017

Current Opinion in Neurology

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Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy

Cited by 353 publications

References 44 publications

RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma

RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma

Identifying neoantigens for use in immunotherapy

Improving diagnosis and management of primary brain tumors

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