Generating Artificial Antigen Presenting Cells for Adoptive T-Cell Therapy

https://openworks.mdanderson.org/sumexp22/1104/thumbnail.jp

Integrative functional genomics identifies RINT1 as a novel GBM oncogene

Large-scale cancer genomics efforts are identifying hundreds of somatic genomic alterations in glioblastoma (GBM). Distinguishing between active driver and neutral passenger alterations requires functional assessment of each gene; therefore, integrating biological weight of evidence with statistical significance for each genomic alteration will enable better prioritization for downstream studies. Here, we demonstrate the feasibility and potential of in vitro functional genomic screens to rapidly and systematically prioritize high-probability candidate genes for in vivo validation. Integration of low-complexity gain- and loss-of-function screens designed on the basis of genomic data identified 6 candidate GBM oncogenes, and RINT1 was validated as a novel GBM oncogene based on its ability to confer tumorigenicity to primary nontransformed murine astrocytes in vivo. Cancer genomics-guided low-complexity genomic screens can quickly provide a functional filter to prioritize high-value targets for further downstream mechanistic and translational studies

Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes

Detection of somatic mutations in human leukocyte antigen (HLA) genes using whole-exome sequencing (WES) is hampered by the high polymorphism of the HLA loci, which prevents alignment of sequencing reads to the human reference genome. We describe a computational pipeline that enables accurate inference of germline alleles of class I HLA-A, B and C genes and subsequent detection of mutations in these genes using the inferred alleles as a reference. Analysis of WES data from 7,930 pairs of tumor and healthy tissue from the same patient revealed 298 nonsilent HLA mutations in tumors from 266 patients. These 298 mutations are enriched for likely functional mutations, including putative loss-of-function events. Recurrence of mutations suggested that these \u27hotspot\u27 sites were positively selected. Cancers with recurrent somatic HLA mutations were associated with upregulation of signatures of cytolytic activity characteristic of tumor infiltration by effector lymphocytes, supporting immune evasion by altered HLA function as a contributory mechanism in cancer

Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8(+) tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non–small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy–induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens

Resistance to checkpoint blockade therapy through inactivation of antigen presentation

Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1

The somatic genomic landscape of glioblastoma

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer

The Somatic Genomic Landscape of Glioblastoma

We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer

Predicted neoantigen load in non-hypermutated endometrial cancers: Correlation with outcome and tumor-specific genomic alterations

Elevated neoantigen load has been previously correlated with improved outcome and response to immune checkpoint blockade in various tumor types. In endometrial cancer, previous studies of neoantigen load prediction have shown that the hypermutated MSI and POLE-mutated tumors harbor significantly higher predicted neoantigen load compared to the hypomutated CN-low/endometrioid and CN-high/serous-like tumors. Here, we report that predicted neoantigen load may be a prognostic factor in hypomutated endometrial cancers, both in CN-low/endometrioid and CN-high/serous-like tumors. Specifically, in the TCGA dataset, CN-low/endometrioid tumors with neoantigen load in the highest tertile were associated with significantly improved progression free survival (PFS) (p = 0.031), while CN-high/serous-like tumors with neoantigen load in the lowest tertile were associated with worse PFS (p = 0.041). Importantly, certain tumor-specific genomic alterations were enriched in tumors with lower neoantigen load, including CTNNB1 mutations in CN-low/endometrioid tumors and MYC amplification and PIK3CA mutations in CN-high/serous-like tumors. These findings suggest that predicted neoantigen load and specific genomic alterations (such as CTNNB1 mutations, MYC amplification and PIK3CA mutations) may be biomarkers of response to immunotherapy in hypomutated endometrial cancers, and argues that these exploratory biomarkers should be incorporated in clinical trials of immune checkpoint blockade in this disease

Predicted neoantigen load in non-hypermutated endometrial cancers: Correlation with outcome and tumor-specific genomic alterations

Elevated neoantigen load has been previously correlated with improved outcome and response to immune checkpoint blockade in various tumor types. In endometrial cancer, previous studies of neoantigen load prediction have shown that the hypermutated MSI and POLE-mutated tumors harbor significantly higher predicted neoantigen load compared to the hypomutated CN-low/endometrioid and CN-high/serous-like tumors. Here, we report that predicted neoantigen load may be a prognostic factor in hypomutated endometrial cancers, both in CN-low/endometrioid and CN-high/serous-like tumors. Specifically, in the TCGA dataset, CN-low/endometrioid tumors with neoantigen load in the highest tertile were associated with significantly improved progression free survival (PFS) (p = 0.031), while CN-high/serous-like tumors with neoantigen load in the lowest tertile were associated with worse PFS (p = 0.041). Importantly, certain tumor-specific genomic alterations were enriched in tumors with lower neoantigen load, including CTNNB1 mutations in CN-low/endometrioid tumors and MYC amplification and PIK3CA mutations in CN-high/serous-like tumors. These findings suggest that predicted neoantigen load and specific genomic alterations (such as CTNNB1 mutations, MYC amplification and PIK3CA mutations) may be biomarkers of response to immunotherapy in hypomutated endometrial cancers, and argues that these exploratory biomarkers should be incorporated in clinical trials of immune checkpoint blockade in this disease