Human Tumor–Associated Macrophages and Neutrophils Regulate Antitumor Antibody Efficacy through Lethal and Sublethal Trogocytosis

Author:

Singhal Sunil1ORCID,Rao Abhishek S.1ORCID,Stadanlick Jason1ORCID,Bruns Kyle1ORCID,Sullivan Neil T.1ORCID,Bermudez Andres1ORCID,Honig-Frand Adam1ORCID,Krouse Ryan1ORCID,Arambepola Sachinthani1ORCID,Guo Emily1ORCID,Moon Edmund K.2ORCID,Georgiou George3ORCID,Valerius Thomas4ORCID,Albelda Steven M.2ORCID,Eruslanov Evgeniy B.1ORCID

Affiliation:

1. 1Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

2. 2Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

3. 3Department of Chemical Engineering, University of Texas at Austin, Austin, Texas.

4. 4Department of Medicine II, Christian Albrechts University and University Hospital Schleswig-Holstein, Kiel, Germany.

Abstract

Abstract The clinical benefits of tumor-targeting antibodies (tAb) are modest in solid human tumors. The efficacy of many tAbs is dependent on Fc receptor (FcR)–expressing leukocytes that bind Fc fragments of tAb. Tumor-associated macrophages (TAM) and neutrophils (TAN) represent the majority of FcR+ effectors in solid tumors. A better understanding of the mechanisms by which TAMs and TANs regulate tAb response could help improve the efficacy of cancer treatments. Here, we found that myeloid effectors interacting with tAb-opsonized lung cancer cells used antibody-dependent trogocytosis (ADT) but not antibody-dependent phagocytosis. During this process, myeloid cells “nibbled off” tumor cell fragments containing tAb/targeted antigen (tAg) complexes. ADT was only tumoricidal when the tumor cells expressed high levels of tAg and the effectors were present at high effector-to-tumor ratios. If either of these conditions were not met, which is typical for solid tumors, ADT was sublethal. Sublethal ADT, mainly mediated by CD32hiCD64hi TAM, led to two outcomes: (i) removal of surface tAg/tAb complexes from the tumor that facilitated tumor cell escape from the tumoricidal effects of tAb; and (ii) acquisition of bystander tAgs by TAM with subsequent cross-presentation and stimulation of tumor-specific T-cell responses. CD89hiCD32loCD64lo peripheral blood neutrophils (PBN) and TAN stimulated tumor cell growth in the presence of the IgG1 anti-EGFR Ab cetuximab; however, IgA anti-EGFR Abs triggered the tumoricidal activity of PBN and negated the stimulatory effect of TAN. Overall, this study provides insights into the mechanisms by which myeloid effectors mediate tumor cell killing or resistance during tAb therapy. Significance: The elucidation of the conditions and mechanisms by which human FcR+ myeloid effectors mediate cancer cell resistance and killing during antibody treatment could help develop improved strategies for treating solid tumors.

Funder

National Cancer Institute

Janssen Pharmaceutica

National Institutes of Health

Publisher

American Association for Cancer Research (AACR)

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