Antibody dependent cell-mediated cytotoxicity selection pressure induces diverse mechanisms of resistance

David J. Zahavi, Rossin Erbe, Yong Wei Zhang, Theresa Guo, Zoe X. Malchiodi, Rachael Maynard, Alexander Lekan, Rosa Gallagher, Julia Wulfkuhle, Emanuel Petricoin, Sandra A. Jablonski, Elana J. Fertig, Louis M. Weiner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Targeted monoclonal antibody therapy has emerged as a powerful therapeutic strategy for cancer. However, only a minority of patients have durable responses and the development of resistance remains a major clinical obstacle. Antibody-dependent cell-mediated cytotoxicity (ADCC) represents a crucial therapeutic mechanism of action; however, few studies have explored ADCC resistance. Using multiple in vitro models of ADCC selection pressure, we have uncovered both shared and distinct resistance mechanisms. Persistent ADCC selection pressure yielded ADCC-resistant cells that are characterized by a loss of NK cell conjugation and this shared resistance phenotype is associated with cell-line dependent modulation of cell surface proteins that contribute to immune synapse formation and NK cell function. We employed single-cell RNA sequencing and proteomic screens to interrogate molecular mechanisms of resistance. We demonstrate that ADCC resistance involves upregulation of interferon/STAT1 and DNA damage response signaling as well as activation of the immunoproteasome. Here, we identify pathways that modulate ADCC sensitivity and report strategies to enhance ADCC-mediated elimination of cancer cells. ADCC resistance could not be reversed with combinatorial treatment approaches. Hence, our findings indicate that tumor cells utilize multiple strategies to inhibit NK cell mediated-ADCC. Future research and development of NK cell-based immunotherapies must incorporate plans to address or potentially prevent the induction of resistance.

Original languageEnglish
Article number2269637
JournalCancer Biology and Therapy
Volume24
Issue number1
DOIs
StatePublished - 2023
Externally publishedYes

Keywords

  • Antibody-dependent cell-mediated cytotoxicity
  • STAT1
  • antibody target
  • cell surface
  • immunoproteasome
  • immunotherapy resistance
  • natural killer cells

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