Patient-derived melanoma organoid models facilitate the assessment of immunotherapiesResearch in context
Lingling Ou,
Shujing Liu,
Huaishan Wang,
Yeye Guo,
Lei Guan,
Longbin Shen,
Ruhui Luo,
David E. Elder,
Alexander C. Huang,
Giorgos Karakousis,
John Miura,
Tara Mitchell,
Lynn Schuchter,
Ravi Amaravadi,
Ahron Flowers,
Haiwei Mou,
Fan Yi,
Wei Guo,
Jina Ko,
Qing Chen,
Bin Tian,
Meenhard Herlyn,
Xiaowei Xu
Affiliations
Lingling Ou
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China
Shujing Liu
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
Huaishan Wang
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
Yeye Guo
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
Lei Guan
Department of Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA
Longbin Shen
The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
Ruhui Luo
Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China
David E. Elder
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
Alexander C. Huang
Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
Giorgos Karakousis
Department of Surgery, University of Pennsylvania, Philadelphia, PA, 19104, USA
John Miura
Department of Surgery, University of Pennsylvania, Philadelphia, PA, 19104, USA
Tara Mitchell
Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
Lynn Schuchter
Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
Ravi Amaravadi
Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
Ahron Flowers
Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
Haiwei Mou
The Wistar Institute, Philadelphia, PA, 19104, USA
Fan Yi
Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, 19104, USA
Wei Guo
Department of Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA
Jina Ko
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
Qing Chen
The Wistar Institute, Philadelphia, PA, 19104, USA
Bin Tian
The Wistar Institute, Philadelphia, PA, 19104, USA
Meenhard Herlyn
The Wistar Institute, Philadelphia, PA, 19104, USA
Xiaowei Xu
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Corresponding author. Department of Pathology and Laboratory Medicine, University of Pennsylvania, 6th Founders Building, 3400 Spruce Street, Philadelphia, PA, 19104.
Summary: Background: Only a minority of melanoma patients experience durable responses to immunotherapies due to inter- and intra-tumoral heterogeneity in melanoma. As a result, there is a pressing need for suitable preclinical models to investigate resistance mechanisms and enhance treatment efficacy. Methods: Here, we report two different methods for generating melanoma patient-derived organoids (MPDOs), one is embedded in collagen gel, and the other is inlaid in Matrigel. MPDOs in Matrigel are used for assessing the therapeutic effects of anti-PD-1 antibodies (αPD-1), autochthonous tumor infiltrating lymphocytes (TILs), and small molecule compounds. MPDOs in collagen gel are used for evaluating the chemotaxis and migratory capacity of TILs. Finding: The MPDOs in collagen gel and Matrigel have similar morphology and immune cell composition to their parental melanoma tissues. MPDOs show inter- and intra-tumoral heterogeneity and contain diverse immune cells such as CD4+, CD8+ T, Treg, CD14+ monocytic, CD15+, and CD11b+ myeloid cells. The tumor microenvironment (TME) in MPDOs is highly immunosuppressive, and the lymphoid and myeloid lineages express similar levels of PD-1, PD-L1, and CTLA-4 as their parental melanoma tissues. Anti-PD-1 antibodies (αPD-1) reinvigorate CD8+ T cells and induce melanoma cell death in the MPDOs. TILs expanded by IL-2 and αPD-1 show significantly lower expression of TIM-3, better migratory capacity and infiltration of autochthonous MPDOs, and more effective killing of melanoma cells than TILs expanded by IL-2 alone or IL-2 with αCD3. A small molecule screen discovers that Navitoclax increases the cytotoxicity of TIL therapy. Interpretation: MPDOs may be used to test immune checkpoint inhibitors and cellular and targeted therapies. Funding: This work was supported by the NIH grants CA114046, CA261608, CA258113, and the Tara Miller Melanoma Foundation.
