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Inhibition of SUMOylation Induces Adaptive Anti-Tumor Immunity Against Pancreatic Cancer through Multiple Effects on the Tumor Microenvironment

ABSTRACT: Inhibition of SUMOylation Induces Adaptive Anti-Tumor Immunity Against Pancreatic Cancer through Multiple Effects on the Tumor Microenvironment

PROVIDER: PRJNA875436 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21380746_1.fastq.gz	Fastqsanger.gz
	SRR21380746_2.fastq.gz	Fastqsanger.gz
	SRR21380747_1.fastq.gz	Fastqsanger.gz
	SRR21380747_2.fastq.gz	Fastqsanger.gz
	SRR21380748_1.fastq.gz	Fastqsanger.gz

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Inhibition of SUMOylation Induces Adaptive Anti-Tumor Immunity Against Pancreatic Cancer through Multiple Effects on the Tumor Microenvironment

Project description:Improvement of pancreatic ductal adenocarcinoma (PDAC) patients’ outcomes require exploration of novel therapeutic mechanisms. Thus far, most studies of PDAC therapies, including those inhibiting small ubiquitin-like modifications (SUMOylation), have focused on PDAC epithelial cell biology. The mechanisms by which SUMOylation impacts PDAC in the context of its tumor microenvironment (TME) are poorly understood. We used clinically relevant orthotopic PDAC mouse models to investigate the effect of SUMOylation inhibition using a specific, clinical stage compound, TAK-981. TAK-981 monotherapy improved survival in immunocompetent mice. However, in contrast to its inhibition of PDAC cell proliferation in vitro, the survival benefit of TAK-981 in vivo is dependent on the presence of T cells. Induction of adaptive anti-tumor immunity is the dominant anti-tumor effect of SUMOylation inhibition in vivo. To elucidate the mechanism of adaptive immunity, we performed comparative single cell transcriptomics analyses of murine and human PDAC tumors, including cancer cells, T cells, tumor associated macrophages (TAM) and cancer associated fibroblasts (CAF), in combination with immunofluorescence, immunohistochemistry, western blots and qPCR. Mechanistically, SUMOylation regulates T cell activation and differentiation. In addition, TAK-981 changed gene expression in TAM, CAF and cancer cells that are likely to enhance the anti-tumor T cell response. These findings provide rationale for combination strategies to augment adaptive immune responses to PDAC that are necessary for durable disease control in PDAC patients.

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Innate and adaptive immunity cross-talk reprograms the tumor microenvironment to an inflammatory hub able to eliminate established poorly immunogenic tumors

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SHP2 Inhibition Abrogates Adaptive Resistance to KRAS-G12C-Inhibition and Remodels the Tumor Microenvironment of KRAS-Mutant Tumors

Project description:KRAS is the most frequently mutated oncogene in human cancer, and KRAS inhibition has been a longtime goal. Recently, inhibitors (G12C-Is) that bind KRAS-G12C-GDP and react with Cys-12 were developed. Using new affinity reagents to monitor KRAS-G12C activation and inhibitor engagement, we found that SHP2 inhibitors (SHP2-Is) increased KRAS-GDP occupancy, enhancing G12C-I efficacy. SHP2-Is abrogated feedback signaling by multiple RTKs and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRAS-G12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) models. The combination of SHP2-I and G12C-I evoked favorable changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using an inhibitor-resistant SHP2 mutant showed that SHP2 inhibition in PDAC cells is required for tumor regression and remodeling of the immune microenvironment, but SHP2-Is also had direct effects on angiogenesis. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies. G12C-Is show significant, but limited, efficacy as single agents, in part because of “adaptive resistance”. We find that combining G12C-Is with SHP2-Is abrogates adaptive resistance and results in favorable changes in the immune microenvironment that potentiate PD-1 blockade in KRAS-mutant malignancies. SHP2-Is also can have direct, context-dependent, effects on tumor vasculature.

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SUMOylation inhibition potentiates CAR T activity against Multiple Myeloma (scRNA-Seq)

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