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Single Cell lineage Tracing Identifies Cancer Testis Antigens as Mediators of Chemoresistance in Small Cell Lung Cancer

ABSTRACT: Small Cell Lung Cancer (SCLC) is often a heterogeneous tumor, where dynamic regulation of key transcription factors can drive multiple populations of phenotypically different cells which contribute differentially to tumor dynamics. This tumor is characterized by a very low 2-year survival rate, high rates of metastasis, and rapid acquisition of chemoresistance. The heterogeneous nature of this tumor makes it difficult to study and to treat, as it is not clear how or when this heterogeneity arises. Here we describe temporal, single-cell analysis of SCLC to investigate tumor initiation and chemoresistance in both SCLC xenografts and in situ SCLC mouse models. We identify an early population of tumor cells with high expression of AP-1 network genes that are critical for tumor growth. Furthermore, we have identified and validated the cancer testis antigens (CTAs) PAGE5 and GAGE2A as mediators of chemoresistance in human SCLC. CTAs have successfully been targeted in other tumor types and may be a promising avenue for targeted therapy in SCLC.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE216182 | GEO | 2023/06/22

REPOSITORIES: GEO

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Project description:Treatment of cancer cells with anti-cancer drugs often fails to achieve complete remission. Yet, such drug treatments may induce alteration in the tumorâs gene expression patterns, including those of Cancer/Testis Antigens (CTA). The degradation products of such antigens can be presented as HLA peptides on the surface of the tumor cells and be developed into anti-cancer immunotherapeutics. For example, the DNA methyl transferase inhibitor, 5-aza-2'-deoxycytidine (Decitabine) has limited anti-tumor efficacy, yet it induces the expression of many genes, including CTAs that are normally silenced in the healthy adult tissues. In this study, the presentation of many new HLA peptides derived from CTAs and induced by Decitabine was demonstrated in three human Glioblastoma cell lines. Such presentation of CTA-derived HLA peptides can be exploited for development of new treatment modalities, combining drug treatment with anti-CTA targeted immunotherapy. The Decitabine-induced HLA peptidomes include many CTAs that are not normally detected in healthy tissues or in cancer cells, unless treated with the drug. In addition, the study included large-scale analyses of the simultaneous effects of Decitabine on the transcriptomes, proteomes and HLA peptidomes of the human Glioblastoma cells. It demonstrates the poor correlations between these three levels of gene expression, both in their total levels and in their response to the drug. The transcriptomes, proteomes and HLA peptidomes of the U-87, T98G and LNT-229 GBM human cell lines were analyzed before and after treatment with Decitabine. Overall, the RNA-Seq transcriptome analyses resulted in the identification of above 26000 transcripts, the proteome analyses identified about 7500 proteins and the HLA class I peptidome analyses resulted in above 25000 identified HLA peptides. Two biological repetitions of the transcriptome, three of the proteome and three of the HLA peptidome were performed with each of the cell lines and treatment, resulting in highly reproducible datasets.

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Single Cell lineage Tracing Identifies Cancer Testis Antigens as Mediators of Chemoresistance in Small Cell Lung Cancer

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