Targeting Loss of p19, not p16, Reprograms Tumor and Systemic Immunity in Pleural Mesothelioma
Presented During:
Sunday, May 7, 2023: 7:15AM - 7:30AM
Los Angeles Convention Center
Posted Room Name:
408B
Abstract No:
101
Submission Type:
Abstract Submission
Authors:
Hyun-Sung Lee (1), Hee-Jin Jang (1), Sung Wook Kang (1), Jong Min Choi (1), Daniela Ramos (1), Claire Lee (1), leandria hosey (1), Bryan Burt (1)
Institutions:
(1) Baylor College of Medicine, Houston, TX
Submitting Author:
♦Hyun-Sung Lee
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Baylor College of Medicine
Baylor College of Medicine
Co-Author(s):
Hee-Jin Jang
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Baylor College of Medicine
Baylor College of Medicine
Sung Wook Kang
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Baylor College of Medicine
Baylor College of Medicine
Jongmin Choi
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Baylor College of Medicine
Baylor College of Medicine
Daniela Ramos
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Baylor College of Medicine
Baylor College of Medicine
Claire Lee
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Baylor College of Medicine
Baylor College of Medicine
leandria hosey
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Baylor College of Medicine
Baylor College of Medicine
*Bryan Burt
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Baylor College of Medicine
Baylor College of Medicine
Presenting Author:
♦Hyun-Sung Lee
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Baylor College of Medicine
Baylor College of Medicine
Abstract:
Objective: Recently we reported that cyclin-dependent kinase inhibitor 2a (CDKN2A)-depleted malignant mesothelioma (MM) is resistant to immune checkpoint blockade (ICB) and CDK4/6 inhibitors (CDK4/6i) improved primary resistance to ICB. CDKN2A, which is the most altered genomic locus in MM, encodes p14 (p19 in mouse) and p16. P16-cyclin D-CDK4/6-Rb and p14-MDM2-p53 pathways inhibit cell cycle and apoptosis, respectively (Fig.1A). However, resistance to CDK4/6i is considered a near-inevitability in a real world. Thus, there are still unmet needs to decipher deeper mechanisms to overcome ICB resistance.
Methods: Given the synteny between human 9p21.3 and murine 4C4 (Fig.1B), p16- or p19-overexpressing mouse AB1 MM cell lines (AB1_p16OE vs. AB1_p19OE) were generated to investigate mechanisms to overcome Cdkn2a-related ICB resistance (Fig.1C). We performed mRNA sequencing for molecular characterization. Furthermore, we compared the alteration of the tumor ecosystems and systemic immunity between AB1_p16OE or AB1_p19OE in immunocompetent BALB/c mice by using imaging and time-of-flight mass cytometry (CyTOF). We also compared the efficacy of dual PD-1 and CTLA-4 blockade on these MM tumors.
Results: Transcriptome analysis showed that AB1_p19OE had a distinct gene expression pattern compared with AB1_p16OE and AB1_wild cell lines. Overexpression of p19 led to the increase of Cd80 and chemokines Cxcl10 and Ccl4, which are involved in lymphocyte recruitment. In contrast, cell cycle-related genes, Cdk2 and Ccne1, and the immunosuppressive cytokine Tgfb1 were markedly decreased in AB1_p19OE cells (Fig.1D). Our in vivo experiments showcased a novel molecular mechanism of regulation of the tumor ecosystems that AB1_p19OE tumors contained lymphocyte aggregates, but AB1_p16OE tumor did not (Fig.1E). We evaluated the topographical expansion of T cells from the tumor to circulation in AB1_p16OE and AB1_p19OE tumors. Mouse CyTOF data showed that PD-1(+)CTLA-4(+) T cells were abundant in tumors (Fig.1F). Interestingly, AB1_p19OE tumors revealed the topographical expansion of CD4 and CD8 effector memory T cells from the tumor to PBMC (Fig.1F) and had a better response to dual ICBs (Fig.1G).
Conclusions: We have identified a novel therapeutic target, p19 in mice or p14 in humans, to sensitize tumors to ICB. This finding could help provide a rationale for combination treatment of ICB with MDM2 inhibitors to restore the function of p14 to treat MM patients with CDKN2A loss.
Methods: Given the synteny between human 9p21.3 and murine 4C4 (Fig.1B), p16- or p19-overexpressing mouse AB1 MM cell lines (AB1_p16OE vs. AB1_p19OE) were generated to investigate mechanisms to overcome Cdkn2a-related ICB resistance (Fig.1C). We performed mRNA sequencing for molecular characterization. Furthermore, we compared the alteration of the tumor ecosystems and systemic immunity between AB1_p16OE or AB1_p19OE in immunocompetent BALB/c mice by using imaging and time-of-flight mass cytometry (CyTOF). We also compared the efficacy of dual PD-1 and CTLA-4 blockade on these MM tumors.
Results: Transcriptome analysis showed that AB1_p19OE had a distinct gene expression pattern compared with AB1_p16OE and AB1_wild cell lines. Overexpression of p19 led to the increase of Cd80 and chemokines Cxcl10 and Ccl4, which are involved in lymphocyte recruitment. In contrast, cell cycle-related genes, Cdk2 and Ccne1, and the immunosuppressive cytokine Tgfb1 were markedly decreased in AB1_p19OE cells (Fig.1D). Our in vivo experiments showcased a novel molecular mechanism of regulation of the tumor ecosystems that AB1_p19OE tumors contained lymphocyte aggregates, but AB1_p16OE tumor did not (Fig.1E). We evaluated the topographical expansion of T cells from the tumor to circulation in AB1_p16OE and AB1_p19OE tumors. Mouse CyTOF data showed that PD-1(+)CTLA-4(+) T cells were abundant in tumors (Fig.1F). Interestingly, AB1_p19OE tumors revealed the topographical expansion of CD4 and CD8 effector memory T cells from the tumor to PBMC (Fig.1F) and had a better response to dual ICBs (Fig.1G).
Conclusions: We have identified a novel therapeutic target, p19 in mice or p14 in humans, to sensitize tumors to ICB. This finding could help provide a rationale for combination treatment of ICB with MDM2 inhibitors to restore the function of p14 to treat MM patients with CDKN2A loss.
THORACIC:
Basic and Translational Research
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