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

Ruella, Marco; Klichinsky, Michael; Kenderian, Saad S.; Shestova, Olga; Ziober, Amy; Kraft, Daniel O.; Feldman, Michael D.; Wasik, Mariusz A.; June, Carl H.; Gill, Saar

doi:10.1158/2159-8290.cd-16-0850

Cited by 160 publications

(146 citation statements)

References 76 publications

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“…B). This suggests, in contrast to previous findings (Locatelli et al , ; Ruella et al , ), that attraction and differentiation are distinct processes regulated by different cytokines or chemokines.…”

Section: Resultscontrasting

confidence: 99%

“…Additionally, Mφ are an integral part of the TME, and the number of CD68‐positive Mφ predicts the patient’s outcome (Scott and Steidl, ). Therefore, targeting the interaction between HL cells and Mφ presents a promising strategy in the treatment of HL (Locatelli et al , ; Ruella et al , ). However, our knowledge of the functions and interactions of Mφ in HL is still limited (Mantovani et al , ; Martinez and Gordon, ; Steidl et al , ).…”

Section: Introductionmentioning

confidence: 99%

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High CD206 levels in Hodgkin lymphoma‐educated macrophages are linked to matrix‐remodeling and lymphoma dissemination

et al. 2020

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Macrophages (Mφ) are abundantly present in the tumor microenvironment and may predict outcome in solid tumors and defined lymphoma subtypes. Mφ heterogeneity, the mechanisms of their recruitment, and their differentiation into lymphoma‐promoting, alternatively activated M2‐like phenotypes are still not fully understood. Therefore, further functional studies are required to understand biological mechanisms associated with human tumor‐associated Mφ (TAM). Here, we show that the global mRNA expression and protein abundance of human Mφ differentiated in Hodgkin lymphoma (HL)‐conditioned medium (CM) differ from those of Mφ educated by conditioned media from diffuse large B‐cell lymphoma (DLBCL) cells or, classically, by macrophage colony‐stimulating factor (M‐CSF). Conditioned media from HL cells support TAM differentiation through upregulation of surface antigens such as CD40, CD163, CD206, and PD‐L1. In particular, RNA and cell surface protein expression of mannose receptor 1 (MRC1)/CD206 significantly exceed the levels induced by classical M‐CSF stimulation in M2‐like Mφ; this is regulated by interleukin 13 to a large extent. Functionally, high CD206 enhances mannose‐dependent endocytosis and uptake of type I collagen. Together with high matrix metalloprotease9 secretion, HL‐TAMs appear to be active modulators of the tumor matrix. Preclinical in ovo models show that co‐cultures of HL cells with monocytes or Mφ support dissemination of lymphoma cells via lymphatic vessels, while tumor size and vessel destruction are decreased in comparison with lymphoma‐only tumors. Immunohistology of human HL tissues reveals a fraction of cases feature large numbers of CD206‐positive cells, with high MRC1 expression being characteristic of HL‐stage IV. In summary, the lymphoma‐TAM interaction contributes to matrix‐remodeling and lymphoma cell dissemination.

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Section: Resultscontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

High CD206 levels in Hodgkin lymphoma‐educated macrophages are linked to matrix‐remodeling and lymphoma dissemination

et al. 2020

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“…For example, TME may develop a number of biochemical and biophysical characteristics that are conducive to tumor progression, such as high interstitial fluid pressure, hypoxia, acidosis, and increased extracellular matrix (ECM) stiffness [1][2][3][4]. Moreover, TME negatively regulate immune effector cells by recruiting myeloid derived suppressor cells (MDSCs), tumor associated macrophages (TAMs), and regulatory T cells (Tregs) to provide an immunosuppressive niche for cancer [5].…”

Section: Introductionmentioning

confidence: 99%

Complex interplay between tumor microenvironment and cancer therapy

Shen

Kang

2018

Front. Med.

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Tumor microenvironment (TME) is comprised of cellular and non-cellular components that exist within and around the tumor mass. The TME is highly dynamic and its importance in different stages of cancer progression has been well recognized. A growing body of evidence suggests that TME also plays pivotal roles in cancer treatment responses. TME is significantly remodeled upon cancer therapies, and such change either enhances the responses or induces drug resistance. Given the importance of TME in tumor progression and therapy resistance, strategies that remodel TME to improve therapeutic responses are under developing. In this review, we provide an overview of the essential components in TME and the remodeling of TME in response to anti-cancer treatments. We also summarize the strategies that aim to enhance therapeutic efficacy by modulating TME.

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“…CAR-T cells have not only been administered concomitantly with agents that modulate the tumour microenvironment 53 , but have also been engineered to directly modulate it, for example through overexpression of heparanase for degradation of the ECM, which resulted in enhanced therapeutic efficacy in a neuroblastoma tumour model 140 . CAFs involved in maintaining the ECM can also be targeted using CARs specific for fibroblast activation protein 141 , and other cancer-associated cells such as TAMs, TECs and T regs can be targeted using CARs directed against tumour-microenvironment-specific antigens 118,[142][143][144] .…”

Section: Nature Biomedical Engineeringmentioning

confidence: 99%

Programming CAR-T cells to kill cancer

2018

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T cells engineered to express chimeric antigen receptors (CARs) that are specific for tumour antigens have led to high complete response rates in patients with haematologic malignancies. Despite this early success, major challenges to the broad application of CAR-T cells as cancer therapies remain, including treatment-associated toxicities and cancer relapse with antigen-negative tumours. Targeting solid tumours with CAR-T cells poses additional obstacles because of the paucity of tumourspecific antigens and the immunosuppressive effects of the tumour microenvironment. To overcome these challenges, T cells can be programmed with genetic modules that increase their therapeutic potency and specificity. In this Review Article, we survey major advances in the engineering of next-generation CAR-T therapies for haematologic cancers and solid cancers, with particular emphasis on strategies for the control of CAR specificity and activity and on approaches for improving CAR-T-cell persistence and overcoming immunosuppression. We also lay out a roadmap for the development of off-the-shelf CAR-T cells.

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

Cited by 160 publications

References 76 publications

High CD206 levels in Hodgkin lymphoma‐educated macrophages are linked to matrix‐remodeling and lymphoma dissemination

High CD206 levels in Hodgkin lymphoma‐educated macrophages are linked to matrix‐remodeling and lymphoma dissemination

Complex interplay between tumor microenvironment and cancer therapy

Programming CAR-T cells to kill cancer

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