Overcoming the Immunosuppressive Tumor Microenvironment of Hodgkin Lymphoma Using Chimeric Antigen Receptor T Cells

Patients with otherwise treatment-resistant Hodgkin lymphoma could benefit from chimeric antigen receptor T-cell (CART) therapy. However, Hodgkin lymphoma lacks CD19 and contains a highly immunosuppressive tumor microenvironment (TME). We hypothesized that in Hodgkin lymphoma, CART should target bot...

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Published inCancer discovery Vol. 7; no. 10; pp. 1154 - 1167
Main Authors Ruella, Marco, Klichinsky, Michael, Kenderian, Saad S, Shestova, Olga, Ziober, Amy, Kraft, Daniel O, Feldman, Michael, Wasik, Mariusz A, June, Carl H, Gill, Saar
Format Journal Article
LanguageEnglish
Published United States 01.10.2017
Subjects
Animals
Cell Differentiation
Cell Line, Tumor
Gene Expression Profiling - methods
Hodgkin Disease - immunology
Hodgkin Disease - therapy
Humans
Interleukin-3 Receptor alpha Subunit - metabolism
K562 Cells
Macrophages - cytology
Macrophages - immunology
Macrophages - pathology
Mice
Recombinant Fusion Proteins - metabolism
T-Lymphocytes - immunology
T-Lymphocytes - transplantation
Tumor Microenvironment
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Summary:Patients with otherwise treatment-resistant Hodgkin lymphoma could benefit from chimeric antigen receptor T-cell (CART) therapy. However, Hodgkin lymphoma lacks CD19 and contains a highly immunosuppressive tumor microenvironment (TME). We hypothesized that in Hodgkin lymphoma, CART should target both malignant cells and the TME. We demonstrated CD123 on both Hodgkin lymphoma cells and TME, including tumor-associated macrophages (TAM). , Hodgkin lymphoma cells convert macrophages toward immunosuppressive TAMs that inhibit T-cell proliferation. In contrast, anti-CD123 CART recognized and killed TAMs, thus overcoming immunosuppression. Finally, we showed in immunodeficient mouse models that CART123 eradicated Hodgkin lymphoma and established long-term immune memory. A novel platform that targets malignant cells and the microenvironment may be needed to successfully treat malignancies with an immunosuppressive milieu. Anti-CD123 chimeric antigen receptor T cells target both the malignant cells and TAMs in Hodgkin lymphoma, thereby eliminating an important immunosuppressive component of the tumor microenvironment. .
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these two authors contributed equally to this paper
ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.CD-16-0850