Lurbinectedin sensitizes PD-L1 blockade therapy by activating STING-IFN signaling in small-cell lung cancer
Lurbinectedin is an approved second-line treatment for small-cell lung cancer (SCLC). SCLC clinical trials combining lurbinectedin with PD-L1 blockade are currently ongoing. However, the immunomodulatory effects of lurbinectedin remain largely unknown. In this study, we demonstrate that lurbinectedin treatment activates the STING pathway, which increases interferon (IFN) signaling, pro-inflammatory chemokines, and major histocompatibility complex class I (MHC-I) in SCLC models. Lurbinectedin treatment augments the anti-tumor immune response of PD-L1 blockade with significant tumor regression in first-line and maintenance settings in SCLC mouse models. In vivo, lurbinectedin treatment increases CD8<sup>+</sup> T cells and M1 macrophages and decreases immunosuppressive M2 macrophages. STING and CD8 depletion reverses the anti-tumor response. Interestingly, our study shows that lurbinectedin treatment upregulates MHC-I/II genes and CD8 in SCLC clinical samples. We provide mechanistic insights into the effect of lurbinectedin on STING-mediated multimodal immune activation and demonstrate that lurbinectedin treatment represents a promising therapeutic strategy to potentiate the efficacy of immunotherapy in SCLC.
Authors
- Hilal Özakıncı (ORCID: https://orcid.org/0000-0001-7921-1000)
- Elisa de Stanchina (ORCID: https://orcid.org/0000-0002-3873-315X)
- Deniz Demircioğlu (ORCID: https://orcid.org/0000-0001-7857-0407)
- Misty Dawn Shields (ORCID: https://orcid.org/0000-0002-7904-5062)
- Lewis E. Tomalin (ORCID: https://orcid.org/0000-0003-4545-7138)
- Avisek Banerjee (ORCID: https://orcid.org/0009-0009-9264-165X)
- Theresa A. Boyle (ORCID: https://orcid.org/0000-0001-5950-3970)
- Triparna Sen (ORCID: https://orcid.org/0000-0003-4673-7481)
- Charles Coleman (ORCID: https://orcid.org/0009-0002-9884-8159)
- Anna S. Tocheva (ORCID: https://orcid.org/0000-0002-3327-0811)
- Subhasree Sridhar (ORCID: https://orcid.org/0000-0001-8189-9836)
- Kedwin Ventura
- Utsav Sen (ORCID: https://orcid.org/0000-0001-7970-0357)
- Yazhini Mahendravarman
- Dan Hasson (ORCID: https://orcid.org/0000-0001-7943-1636)
- Subhamoy Chakraborty
- Vrinda Jethalia
- Konrad Snioch
Institutions
- Indiana University Health (US)
- Memorial Sloan Kettering Cancer Center (US)
- Moffitt Cancer Center (US)
- Indiana University – Purdue University Indianapolis (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101852
- Citations
- 8
- Primary Topic
- Lung Cancer Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 2.26
Funders
- Bristol-Myers Squibb
- Moffitt Cancer Center
- Jazz Pharmaceuticals
- Georgia Clinical and Translational Science Alliance
- National Institutes of Health
- National Cancer Institute
- National Center for Advancing Translational Sciences
- Congressionally Directed Medical Research Programs