Macrophage-Mediated Trogocytosis Leads to Death of Antibody-Opsonized Tumor Cells

Velmurugan, Ramraj; Challa, Dilip K.; Ram, Sripad; Ober, Raimund J.; Ward, E. Sally

doi:10.1158/1535-7163.mct-15-0335

Cited by 79 publications

(90 citation statements)

References 49 publications

(65 reference statements)

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“…Moreover, daratumumab-mediated trogocytosis may impair the ability of MM cells to interact with the protective BM microenvironment by reducing expression of several adhesion proteins on MM cells, including CD38 which also functions as adhesion molecule(43). Finally, even the process of trogocytosis itself may lead to death of antibody-opsonized tumor cells as a result of membrane damage as well as loss of the target antigen and other important molecules(44). All these possibilities need to be investigated in future studies.…”

Section: Discussionmentioning

confidence: 99%

Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab

Krejcik

Frerichs

Nijhof

et al. 2017

Clinical Cancer Research

143

159

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Purpose Daratumumab treatment results in a marked reduction of CD38 expression on multiple myeloma (MM) cells. The aim of this study was to investigate the clinical implications and the underlying mechanisms of daratumumab-mediated CD38 reduction. Experimental design We evaluated the effect of daratumumab alone or in combination with lenalidomide-dexamethasone, on CD38 levels of MM cells and non-tumor immune cells in the GEN501 study (daratumumab monotherapy) and the GEN503 study (daratumumab combined with lenalidomide-dexamethasone). In vitro assays were also performed. Results In both trials daratumumab reduced CD38 expression on MM cells within hours after starting the first infusion, regardless of depth and duration of the response. In addition, CD38 expression on non-tumor immune cells, including NK-, T- B-cells and monocytes, was also reduced irrespective of alterations in their absolute numbers during therapy. In-depth analyses revealed that CD38 levels of MM cells were only reduced in the presence of complement or effector cells, suggesting that the rapid elimination of CD38high MM cells can contribute to CD38 reduction. In addition, we discovered that daratumumab-CD38 complexes and accompanying cell membrane were actively transferred from MM cells to monocytes and granulocytes. This process of trogocytosis was also associated with reduced surface levels of some other membrane proteins including CD49d, CD56, and CD138. Conclusion Daratumumab rapidly reduced CD38 expression levels, at least in part, through trogocytosis. Importantly, all these effects also occurred in patients with deep and durable responses, thus excluding CD38 reduction alone as a mechanism of daratumumab resistance.

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Section: Discussionmentioning

confidence: 99%

Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab

Krejcik

Frerichs

Nijhof

et al. 2017

Clinical Cancer Research

143

159

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“…Fc-mediated effector functions such as ADCP, ADCC, and CDC can contribute to the therapeutic efficacy of EGFR antibodies (27). Frustrated phagocytosis leading to tumor cell death (trogocytosis/trogoptosis) is a documented mechanism of tumor cell killing by macrophages (42) and has recently been described as PMN's major tumor cell killing mechanism (29). Individual EGFR antibodies do not trigger CDC against human tumor cells, unless they are specifically Fc engineered (43,44).…”

Section: Discussionmentioning

confidence: 99%

Immune Effector Functions of Human IgG2 Antibodies against EGFR

Rösner

Kahle

Montenegro

et al. 2019

Molecular Cancer Therapeutics

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Three FDA-approved epidermal growth factor receptor (EGFR) antibodies (cetuximab, panitumumab, necitumumab) are clinically available to treat patients with different types of cancers. Interestingly, panitumumab is of human IgG2 isotype, which is often considered to have limited immune effector functions. Unexpectedly, our studies unraveled that human IgG2 antibodies against EGFR mediated effective CDC when combined with another noncrossblocking EGFR antibody. This second antibody could be of human IgG1 or IgG2 isotype. Furthermore, EGFR antibodies of human IgG2 isotype were highly potent in recruiting myeloid effector cells such as M1 macrophages and PMN for tumor cell killing by ADCC. Tumor cell killing by PMN was more effective with IgG2 than with IgG1 antibodies if tumor cells expressed lower levels of EGFR. Additionally, lower expression levels of the "don't eat me" molecule CD47 on tumor cells enabled ADCC also by M2 macrophages, and improved PMN and macrophage-mediated ADCC. A TCGA enquiry revealed broadly varying CD47 expression levels across different solid tumor types. Together, these results demonstrate that human IgG2 antibodies against EGFR can promote significant Fc-mediated effector functions, which may contribute to their clinical efficacy. The future challenge will be to identify clinical situations in which myeloid effector cells can optimally contribute to antibody efficacy.

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“…Nonetheless, the therapeutic efficacy of these antibodies may be limited by counter mechanisms including antigenic modulation and trogocytosis, both of which remove antibody-antigen complexes off target cell plasma membrane [90][93]. Of note, trogocytosis has recently been shown to induce cell death complimentary to whole cell phagocytosis [94]. To further improve ADCP activity, the Fc region of tumor-targeted antibodies could be engineered to increase its interaction with activatory Fc receptors, most importantly FcγRIIa, on macrophages [95].…”

Section: Pharmacological Modulation Of Macrophages/tamsmentioning

confidence: 99%

Progress in tumor-associated macrophage (TAM)-targeted therapeutics

Ngambenjawong

Gustafson

Pun

2017

Advanced Drug Delivery Reviews

606

484

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As an essential innate immune population for maintaining body homeostasis and warding off foreign pathogens, macrophages display high plasticity and perform diverse supportive functions specialized to different tissue compartments. Consequently, aberrance in macrophage functions contributes substantially to progression of several diseases including cancer, fibrosis, and diabetes. In the context of cancer, tumor-associated macrophages (TAMs) in tumor microenvironment (TME) typically promote cancer cell proliferation, immunosuppression, and angiogenesis in support of tumor growth and metastasis. Oftentimes, the abundance of TAMs in tumor is correlated with poor disease prognosis. Hence, significant attention has been drawn towards development of cancer immunotherapies targeting these TAMs; either depleting them from tumor, blocking their pro-tumoral functions, or restoring their immunostimulatory/tumoricidal properties. This review aims to introduce readers to various aspects in development and evaluation of TAM-targeted therapeutics in pre-clinical and clinical stages.

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Macrophage-Mediated Trogocytosis Leads to Death of Antibody-Opsonized Tumor Cells

Cited by 79 publications

References 49 publications

Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab

Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab

Immune Effector Functions of Human IgG2 Antibodies against EGFR

Progress in tumor-associated macrophage (TAM)-targeted therapeutics

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