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Peptide vaccine targeting mutated GNAS: a potential novel treatment for pseudomyxoma peritonei
Kjersti Flatmark1,2,3, Annette Torgunrud2,3, Karianne G Fleten2,3
1Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway kjersti.flatmark@rr-research.no.
Background:
Pseudomyxoma peritonei (PMP) is a rare, slow-growing abdominal cancer with no efficacious treatment options in non-resectable and recurrent cases. Otherwise, rare activating mutations in the GNAS oncogene are remarkably frequent in PMP and the mutated gene product, guanine nucleotide-binding protein α subunit (Gsα), is a potential tumor neoantigen, presenting an opportunity for targeting by a therapeutic cancer vaccine.
Methods:
Tumor and blood samples were collected from 25 patients undergoing surgery for PMP (NCT02073500). GNAS mutation analysis was performed by next-generation targeted sequencing or digital droplet PCR. Responses to stimulation with Gsα mutated (point mutations R201H and R201C) 30 mer peptides were analyzed in peripheral blood T cells derived from patients with PMP and healthy donors. Fresh PMP tumor samples were analyzed by mass cytometry using a panel of 35 extracellular markers, and cellular subpopulations were clustered and visualized using the visual stochastic network embedding analysis tool.
Results:
GNAS mutations were detected in 22/25 tumor samples (88%; R201H and R201C mutations detected in 16 and 6 cases, respectively). Strong T cell proliferation against Gsα mutated peptides was observed in 18/24 patients with PMP. Mass cytometry analysis of tumor revealed infiltration of CD3 +T cells in most samples, with variable CD4+:CD8 + ratios. A large proportion of T cells expressed immune checkpoint molecules, in particular programmed death receptor-1 and T cell immunoreceptor with Ig and ITIM, indicating that these T cells were antigen experienced.
Conclusion:
These findings point to the existence of a pre-existing immunity in patients with PMP towards mutated Gsα, which has been insufficient to control tumor growth, possibly because of inhibition of antitumor T cells by upregulation of immune checkpoint molecules. The results form a rationale for exploring peptide vaccination with Gsα peptides in combination with immune checkpoint inhibiton as a possible curative treatment for PMP and other GNAS mutated cancers.
Insights
Pseudomyxoma peritonei (PMP) patients show T cell immunity against GNAS mutations. Combining GNAS peptide vaccines with immune checkpoint inhibitors may offer a new curative treatment for PMP and other GNAS-mutated cancers.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Pseudomyxoma peritonei (PMP) is a rare abdominal cancer lacking effective treatments for unresectable or recurrent cases.
- Activating mutations in the GNAS oncogene are frequent in PMP, and the mutated guanine nucleotide-binding protein α subunit (Gsα) serves as a potential tumor neoantigen.
- The GNAS mutation presents a therapeutic opportunity for targeting PMP with a cancer vaccine.
Purpose of the Study:
- To investigate the presence and nature of T cell immunity against GNAS mutations in PMP patients.
- To analyze the tumor microenvironment in PMP, focusing on T cell infiltration and immune checkpoint molecule expression.
- To establish a rationale for GNAS-targeted peptide vaccination combined with immune checkpoint inhibition for PMP treatment.
Main Methods:
- Collected tumor and blood samples from 25 PMP patients.
- Analyzed GNAS mutation status using next-generation sequencing and digital droplet PCR.
- Assessed T cell proliferation responses to mutated Gsα peptides and analyzed tumor immune infiltrates via mass cytometry.
Main Results:
- GNAS mutations (R201H/R201C) were found in 88% of PMP tumor samples.
- A significant proportion of PMP patients (18/24) exhibited strong T cell proliferation against mutated Gsα peptides.
- Mass cytometry revealed T cell infiltration in tumors, with many T cells expressing immune checkpoint molecules like PD-1, indicating antigen experience.
Conclusions:
- PMP patients possess pre-existing immunity against mutated Gsα, but it's insufficient to control tumor growth, likely due to immune checkpoint upregulation.
- The findings support exploring GNAS peptide vaccination combined with immune checkpoint inhibitors as a potential curative strategy for PMP.
- This approach may also be applicable to other cancers harboring GNAS mutations.
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