Homozygous Co-Deletion of Type I Interferons and CDKN2A Genes in Thoracic Cancers: Potential Consequences for Therapy

Grard, Marion; Chatelain, Camille; Delaunay, Tiphaine; Pons‐Tostivint, Elvire; Bennouna, Jaafar; Fonteneau, Jean-François

doi:10.3389/fonc.2021.695770

Cited by 10 publications

(6 citation statements)

References 66 publications

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“…We found that HD of type I interferon ( IFN ‐ I ) genes was the most frequent type of copy‐number variation (CNV) accompanying CDKN2A and CDKN2B HD in LUAD. A previous report suggested that homozygous co‐deletion of IFN‐I and CDKN2A is a potential biomarker for therapy in thoracic cancers [ 16 ]. There are 16 IFN ‐ I genes located on chromosome 9p21 that share a common receptor, induce immune response, and participate in cell antiviral and anti‐tumor defense.…”

Section: Introductionmentioning

confidence: 99%

Co‐occurrence of CDKN2A/B and IFN‐I homozygous deletions correlates with an immunosuppressive phenotype and poor prognosis in lung adenocarcinoma

Peng

Chen

Song³

et al. 2022

Molecular Oncology

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Homozygous deletion (HD) of CDKN2A and CDKN2B (CDKN2A/BHD) is the most frequent copy‐number variation (CNV) in lung adenocarcinoma (LUAD). CDKN2A/BHD has been associated with poor outcomes in LUAD; however, the mechanisms of its prognostic effect remain unknown. We analyzed genome, transcriptome, and clinical data from 517 patients with LUAD from the Cancer Genome Atlas (TCGA) and from 788 primary LUAD tumor and matched control samples from the MSK‐IMPACT clinical cohort. CDKN2A/BHD was present in 19.1% of the TCGA‐LUAD cohort and in 5.7% of the MSK‐IMPACT cohort. CDKN2A/BHD patients had shorter disease‐free survival and overall survival compared with CDKN2A/BWT individuals in both cohorts. Differences in clinical features did not influence the outcomes in the CDKN2A/BHD population. Mutation analyses showed that overall tumor mutational burden and mutations in classical drivers such as EGFR and RB1 were not associated with CDKN2A/BHD. In contrast, homozygous deletion of type I interferons (IFN‐IHD) frequently co‐occurred with CDKN2A/BHD. CDKN2A/B and IFN‐I are co‐located in the same p21.3 region of chromosome 9. The co‐occurrence of CDKN2A/BHD and IFN‐IHD was not related to whole‐genome doubling, chromosome instability, or aneuploidy. Patients with co‐occurring CDKN2A/BHD and IFN‐IHD had shorter disease‐free survival and overall survival compared with CDKN2A/BWT patients. CDKN2A/BHDIFN‐IHD had downregulated several key immune response pathways, suggesting that poor prognosis in CDKN2A/BHD LUAD could potentially be attributed to an immunosuppressive tumor microenvironment as a result of IFN‐I depletion.

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Section: Introductionmentioning

confidence: 99%

Co‐occurrence of CDKN2A/B and IFN‐I homozygous deletions correlates with an immunosuppressive phenotype and poor prognosis in lung adenocarcinoma

Peng

Chen

Song³

et al. 2022

Molecular Oncology

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“…CDKN2A is also a classical genomic alteration of mesothelioma (35). However, what is less known is the usual loss of type I interferon genes together with CDKN2A losses (37). Interestingly, those CDKN2A associated type I interferon losses have been shown to present altered immune gene signatures in tumors (38).…”

Section: Genomic Somatic Copy Number Alterations Correlate With Plasm...mentioning

confidence: 99%

Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma

et al. 2023

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Cancer immunotherapy combinations have recently shown to improve the overall survival of advanced mesotheliomas especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas primary resistance to immunotherapy and anti-angiogenics by testing the combination of pembrolizumab, an anti-PD-1 antibody, and nintedanib, a pan anti-angiogenic tyrosine kinase inhibitor (TKI), in the multi-center PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T-cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy number alterations in their tumors that correlated with high blood and tumor levels of IL-6 and CXCL8. Those pro-inflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T-cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology.

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“…Tumor cells with reduced IFN-I expression may evade immune cells due to a lack of IFN-α and - ß cross talk to the immune system. Loss or reduction of this central coordinator mechanism for the tumor–immune interaction would contribute to immune escape and ICI resistance ( Grard et al, 2021 ), especially in the context of tumor-targeted combination approaches.…”

Section: Genetic Features Of Pdac May Influence Immune Cell Functionmentioning

confidence: 99%

Modulation of Type I Interferon Responses to Influence Tumor-Immune Cross Talk in PDAC

Cattolico

Bailey

Barry

2022

Front. Cell Dev. Biol.

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Immunotherapy has revolutionized the treatment of many cancer types. However, pancreatic ductal adenocarcinomas (PDACs) exhibit poor responses to immune checkpoint inhibitors with immunotherapy-based trials not generating convincing clinical activity. PDAC tumors often have low infiltration of tumor CD8+ T cells and a highly immunosuppressive microenvironment. These features classify PDAC as immunologically “cold.” However, the presence of tumor T cells is a favorable prognostic feature in PDAC. Intrinsic tumor cell properties govern interactions with the immune system. Alterations in tumor DNA such as genomic instability, high tumor mutation burden, and/or defects in DNA damage repair are associated with responses to both immunotherapy and chemotherapy. Cytotoxic or metabolic stress produced by radiation and/or chemotherapy can act as potent immune triggers and prime immune responses. Damage- or stress-mediated activation of nucleic acid-sensing pathways triggers type I interferon (IFN-I) responses that activate innate immune cells and natural killer cells, promote maturation of dendritic cells, and stimulate adaptive immunity. While PDAC exhibits intrinsic features that have the potential to engage immune cells, particularly following chemotherapy, these immune-sensing mechanisms are ineffective. Understanding where defects in innate immune triggers render the PDAC tumor–immune interface less effective, or how T-cell function is suppressed will help develop more effective treatments and harness the immune system for durable outcomes. This review will focus on the pivotal role played by IFN-I in promoting tumor cell–immune cell cross talk in PDAC. We will discuss how PDAC tumor cells bypass IFN-I signaling pathways and explore how these pathways can be co-opted or re-engaged to enhance the therapeutic outcome.

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Homozygous Co-Deletion of Type I Interferons and CDKN2A Genes in Thoracic Cancers: Potential Consequences for Therapy

Cited by 10 publications

References 66 publications

Co‐occurrence of CDKN2A/B and IFN‐I homozygous deletions correlates with an immunosuppressive phenotype and poor prognosis in lung adenocarcinoma

Co‐occurrence of CDKN2A/B and IFN‐I homozygous deletions correlates with an immunosuppressive phenotype and poor prognosis in lung adenocarcinoma

Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti–PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma

Modulation of Type I Interferon Responses to Influence Tumor-Immune Cross Talk in PDAC

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