Intratumoral STING agonist reverses immune evasion in PD-(L)1-refractory Merkel cell carcinoma: mechanistic insights from detailed biomarker analyses
Background Antibodies blocking programmed death (PD)-1 or its ligand (PD-L1) have revolutionized cancer care, but many patients do not experience durable benefits. Novel treatments to stimulate antitumor immunity are needed in the PD-(L)1 refractory setting. The stimulator of interferon genes (STING...
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BMJ Publishing Group
2024-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/10/e009803.full |
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| author | Shailender Bhatia Paul Nghiem Rima Kulikauskas Candice Church David M Koelle Lisa Tachiki Kimberly Smythe Thomas Pulliam Shira Tabachnick-Cherny Saumya Jani Peter H Goff Rashmi Bhakuni Brandon W Seaton |
| author_facet | Shailender Bhatia Paul Nghiem Rima Kulikauskas Candice Church David M Koelle Lisa Tachiki Kimberly Smythe Thomas Pulliam Shira Tabachnick-Cherny Saumya Jani Peter H Goff Rashmi Bhakuni Brandon W Seaton |
| author_sort | Shailender Bhatia |
| collection | DOAJ |
| description | Background Antibodies blocking programmed death (PD)-1 or its ligand (PD-L1) have revolutionized cancer care, but many patients do not experience durable benefits. Novel treatments to stimulate antitumor immunity are needed in the PD-(L)1 refractory setting. The stimulator of interferon genes (STING) protein, an innate sensor of cytoplasmic DNA, is a promising target with several agonists in development. However, response rates in most recent clinical trials have been low and mechanisms of response remain unclear. We report detailed biomarker analyses in a patient with anti-PD-L1 refractory, Merkel cell polyomavirus (MCPyV)-positive, metastatic Merkel cell carcinoma (MCC) who was treated with an intratumoral (IT) STING agonist (ADU-S100) plus intravenous anti-PD-1 antibody (spartalizumab) and experienced a durable objective response with regression of both injected and non-injected lesions.Methods We analyzed pretreatment and post-treatment tumor and peripheral blood samples from our patient with single-cell RNA sequencing, 30-parameter flow cytometry, T cell receptor sequencing, and multiplexed immunohistochemistry. We analyzed cancer-specific CD8 T cells using human leukocyte antigen (HLA)-I tetramers loaded with MCPyV peptides. We also analyzed STING expression and signaling in the tumor microenvironment (TME) of 88 additional MCC tumor specimens and in MCC cell lines.Results We observed high levels of MCPyV-specific T cells (12% of T cells) in our patient’s tumor at baseline. These cancer-specific CD8 T cells exhibited characteristics of exhaustion including high TOX and low TCF1 proteins. Following treatment with STING-agonist plus anti-PD-1, IT CD8 T cells expanded threefold. We also observed evidence of likely improved antigen presentation in the MCC TME (greater than fourfold increase of HLA-I-positive cancer cells). STING expression was not detected in any cancer cells within our patient’s tumor or in 88 other MCC tumors, however high STING expression was observed in immune and stromal cells within all 89 MCC tumors.Conclusions Our results suggest that STING agonists may be able to work indirectly in MCC via signaling through immune and stromal cells in the TME, and may not necessarily need STING expression in the cancer cells. This approach may be particularly effective in tumors that are already infiltrated by inflammatory cells in the TME but are evading immune detection via HLA-I downregulation. |
| format | Article |
| id | doaj-art-5d97ea745ca64b74a14af5ba8a97b20b |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-5d97ea745ca64b74a14af5ba8a97b20b2025-08-20T02:27:46ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-10-01121010.1136/jitc-2024-009803Intratumoral STING agonist reverses immune evasion in PD-(L)1-refractory Merkel cell carcinoma: mechanistic insights from detailed biomarker analysesShailender Bhatia0Paul Nghiem1Rima Kulikauskas2Candice Church3David M Koelle4Lisa Tachiki5Kimberly Smythe6Thomas Pulliam7Shira Tabachnick-Cherny8Saumya Jani9Peter H Goff10Rashmi Bhakuni11Brandon W Seaton122Fred Hutchinson Cancer Center, Seattle, WA, USADepartment of Dermatology, University of Washington School of Medicine, Seattle, Washington, USADepartment of Dermatology, University of Washington School of Medicine, Seattle, Washington, USADepartment of Dermatology, University of Washington School of Medicine, Seattle, Washington, USAFred Hutchinson Cancer Center, Seattle, Washington, USAFred Hutchinson Cancer Center, Seattle, Washington, USAFred Hutchinson Cancer Center, Seattle, Washington, USA3Department of Dermatology, University of Washington, Seattle, WA, USADepartment of Dermatology, University of Washington School of Medicine, Seattle, Washington, USA6Department of Medicine, University of Washington, Seattle, WA, USAFred Hutchinson Cancer Center, Seattle, Washington, USA1University of Washington, Seattle, WA, USAFred Hutchinson Cancer Center, Seattle, Washington, USABackground Antibodies blocking programmed death (PD)-1 or its ligand (PD-L1) have revolutionized cancer care, but many patients do not experience durable benefits. Novel treatments to stimulate antitumor immunity are needed in the PD-(L)1 refractory setting. The stimulator of interferon genes (STING) protein, an innate sensor of cytoplasmic DNA, is a promising target with several agonists in development. However, response rates in most recent clinical trials have been low and mechanisms of response remain unclear. We report detailed biomarker analyses in a patient with anti-PD-L1 refractory, Merkel cell polyomavirus (MCPyV)-positive, metastatic Merkel cell carcinoma (MCC) who was treated with an intratumoral (IT) STING agonist (ADU-S100) plus intravenous anti-PD-1 antibody (spartalizumab) and experienced a durable objective response with regression of both injected and non-injected lesions.Methods We analyzed pretreatment and post-treatment tumor and peripheral blood samples from our patient with single-cell RNA sequencing, 30-parameter flow cytometry, T cell receptor sequencing, and multiplexed immunohistochemistry. We analyzed cancer-specific CD8 T cells using human leukocyte antigen (HLA)-I tetramers loaded with MCPyV peptides. We also analyzed STING expression and signaling in the tumor microenvironment (TME) of 88 additional MCC tumor specimens and in MCC cell lines.Results We observed high levels of MCPyV-specific T cells (12% of T cells) in our patient’s tumor at baseline. These cancer-specific CD8 T cells exhibited characteristics of exhaustion including high TOX and low TCF1 proteins. Following treatment with STING-agonist plus anti-PD-1, IT CD8 T cells expanded threefold. We also observed evidence of likely improved antigen presentation in the MCC TME (greater than fourfold increase of HLA-I-positive cancer cells). STING expression was not detected in any cancer cells within our patient’s tumor or in 88 other MCC tumors, however high STING expression was observed in immune and stromal cells within all 89 MCC tumors.Conclusions Our results suggest that STING agonists may be able to work indirectly in MCC via signaling through immune and stromal cells in the TME, and may not necessarily need STING expression in the cancer cells. This approach may be particularly effective in tumors that are already infiltrated by inflammatory cells in the TME but are evading immune detection via HLA-I downregulation.https://jitc.bmj.com/content/12/10/e009803.full |
| spellingShingle | Shailender Bhatia Paul Nghiem Rima Kulikauskas Candice Church David M Koelle Lisa Tachiki Kimberly Smythe Thomas Pulliam Shira Tabachnick-Cherny Saumya Jani Peter H Goff Rashmi Bhakuni Brandon W Seaton Intratumoral STING agonist reverses immune evasion in PD-(L)1-refractory Merkel cell carcinoma: mechanistic insights from detailed biomarker analyses Journal for ImmunoTherapy of Cancer |
| title | Intratumoral STING agonist reverses immune evasion in PD-(L)1-refractory Merkel cell carcinoma: mechanistic insights from detailed biomarker analyses |
| title_full | Intratumoral STING agonist reverses immune evasion in PD-(L)1-refractory Merkel cell carcinoma: mechanistic insights from detailed biomarker analyses |
| title_fullStr | Intratumoral STING agonist reverses immune evasion in PD-(L)1-refractory Merkel cell carcinoma: mechanistic insights from detailed biomarker analyses |
| title_full_unstemmed | Intratumoral STING agonist reverses immune evasion in PD-(L)1-refractory Merkel cell carcinoma: mechanistic insights from detailed biomarker analyses |
| title_short | Intratumoral STING agonist reverses immune evasion in PD-(L)1-refractory Merkel cell carcinoma: mechanistic insights from detailed biomarker analyses |
| title_sort | intratumoral sting agonist reverses immune evasion in pd l 1 refractory merkel cell carcinoma mechanistic insights from detailed biomarker analyses |
| url | https://jitc.bmj.com/content/12/10/e009803.full |
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