Anti-PD-1/PD-L1 therapy augments lenvatinib's efficacy by favorably altering the immune microenvironment of murine anaplastic thyroid cancer
Viswanath Gunda
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
V.G. and B.G. contributed equally to this work.Search for more papers by this authorBenjamin Gigliotti
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
V.G. and B.G. contributed equally to this work.Search for more papers by this authorTameem Ashry
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorDorothy Ndishabandi
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorMichael McCarthy
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorZhiheng Zhou
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorSalma Amin
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorKyu Eun Lee
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorTabea Stork
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorLori Wirth
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorGordon J. Freeman
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorAlessandro Alessandrini
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorCorresponding Author
Sareh Parangi
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Correspondence to: Sareh Parangi, MD, Harvard Medical School, Massachusetts General Hospital, Department of Surgery, Division of General and Gastrointestinal Surgery, Wang Ambulatory Care Center 460, 15 Parkman Street, Boston, MA 02115, Tel.: 617-643-4806; Fax: 617-643-4802; E-mail: [email protected]Search for more papers by this authorViswanath Gunda
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
V.G. and B.G. contributed equally to this work.Search for more papers by this authorBenjamin Gigliotti
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
V.G. and B.G. contributed equally to this work.Search for more papers by this authorTameem Ashry
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorDorothy Ndishabandi
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorMichael McCarthy
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorZhiheng Zhou
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorSalma Amin
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorKyu Eun Lee
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorTabea Stork
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorLori Wirth
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorGordon J. Freeman
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorAlessandro Alessandrini
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Search for more papers by this authorCorresponding Author
Sareh Parangi
Department of Surgery, Division of General and Gastrointestinal Surgery, Harvard Medical School, Massachusetts General Hospital, Wang Ambulatory Care Center, 460, 15 Parkman Street, Boston, MA
Correspondence to: Sareh Parangi, MD, Harvard Medical School, Massachusetts General Hospital, Department of Surgery, Division of General and Gastrointestinal Surgery, Wang Ambulatory Care Center 460, 15 Parkman Street, Boston, MA 02115, Tel.: 617-643-4806; Fax: 617-643-4802; E-mail: [email protected]Search for more papers by this authorAbstract
Patients with anaplastic thyroid cancer (ATC) have an extremely poor prognosis despite multimodal therapy with surgery and chemoradiation. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, as well as checkpoint inhibitors targeting the programmed cell death pathway, have proven effective in some patients with advanced thyroid cancer. Combination of these therapies is a potential means to boost effectiveness and minimize treatment resistance in ATC. We utilized our novel immunocompetent murine model of orthotopic ATC to demonstrate that lenvatinib led to significant tumor shrinkage and increased survival, while combination therapy led to dramatic improvements in both. Lenvatinib monotherapy increased tumor-infiltrating macrophages, CD8+ T-cells, regulatory T-cells, and most notably, polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs). While both combination therapies led to further increases in CD8+ T-cells, only the lenvatinib and anti-PD-1 combination decreased PMN-MDSCs. PMN-MDSC expansion was also seen in the blood of mice and one patient receiving lenvatinib therapy for ATC. RNA-Seq of the ATC cell line used in our mouse model demonstrated that lenvatinib has multifaceted effects on angiogenesis, response to hypoxia, the epithelial-to-mesenchymal transition, and on multiple pathways implicated in inflammation and host immunity. Combination of lenvatinib with anti-Gr-1 antibody ameliorated lenvatinib's expansion of MDSCs and significantly improved lenvatinib's anti-tumor effect. These data suggest that MDSCs play a negative role in ATC's response to lenvatinib and support future study of their role as a potential biomarker and treatment target.
Abstract
What's new?
Anaplastic thyroid cancer (ATC) is a rare malignancy that is notoriously aggressive. Fatality from ATC remains high, despite advances in multimodal therapy. Here, the authors investigated combination therapy employing tyrosine kinase inhibitors and checkpoint inhibitors as a novel treatment strategy in ATC. In a mouse model of orthotopic ATC, combined treatment with the tyrosine kinase inhibitor lenvatinib and an anti-PD-1/PD-L1 checkpoint inhibitor was found to dramatically reduce tumor volume and improve survival. While lenvatinib monotherapy was associated with increased tumor-infiltrating and circulating myeloid-derived suppressor cells (MDSCs), the depletion of MDSCs via combination therapy significantly augmented lenvatinib's effectiveness.
Supporting Information
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