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Updated: Jul 29, 2025
Author Spotlight: Recreating Melanoma Complexity with Patient-Derived Organoids for Immunotherapy Evaluation
Published on: September 6, 2024
Patient-derived melanoma organoid models facilitate the assessment of immunotherapies
Lingling Ou1, Shujing Liu2, Huaishan Wang2
1Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China.
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.
Insights
Melanoma patient-derived organoids (MPDOs) were developed to model tumor heterogeneity and test immunotherapies. These models effectively predict responses to anti-PD-1 antibodies and identify novel therapeutic combinations for melanoma.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Melanoma patient responses to immunotherapy are limited by tumor heterogeneity.
- There is a need for preclinical models to study melanoma resistance mechanisms and improve treatment efficacy.
Purpose of the Study:
- To develop and characterize melanoma patient-derived organoids (MPDOs) as preclinical models.
- To assess the utility of MPDOs in evaluating immunotherapies and targeted agents.
Main Methods:
- Two methods for generating MPDOs were established: one in collagen gel and another in Matrigel.
- MPDOs were used to assess anti-PD-1 antibodies, tumor-infiltrating lymphocytes (TILs), and small molecule compounds.
- MPDOs in collagen gel were used to evaluate TIL chemotaxis and migration.
Main Results:
- MPDOs recapitulated the morphology, heterogeneity, and immunosuppressive tumor microenvironment of parental melanoma tissues.
- Anti-PD-1 antibodies reactivated CD8+ T cells and induced melanoma cell death in MPDOs.
- TILs expanded with anti-PD-1 showed enhanced anti-melanoma activity compared to other expansion methods; Navitoclax increased TIL therapy efficacy.
Conclusions:
- Melanoma patient-derived organoids serve as valuable models for testing immune checkpoint inhibitors.
- MPDOs can be utilized to evaluate cellular therapies and targeted treatments for melanoma.
