Therapeutic targeting of checkpoint receptors within the dnam1 axis

Zoya Alteber, Maya F. Kotturi, Sarah Whelan, Sudipto Ganguly, Emmanuel Weyl, Drew M. Pardoll, John Hunter, Eran Ophir

Research output: Contribution to journalReview articlepeer-review


Therapeutic antibodies targeting the CTLA4/PD-1 pathways have revolutionized cancer immunotherapy by eliciting durable remission in patients with cancer. How-ever, relapse following early response, attributable to primary and adaptive resistance, is frequently observed. Additional immunomodulatory pathways are being studied in patients with primary or acquired resistance to CTLA4 or PD-1 blockade. The DNAM1 axis is a potent coregulator of innate and adaptive immunity whose other components include the immunoglobulin receptors TIGIT, PVRIG, and CD96, and their nectin and nectin-like ligands. We review the basic biology and therapeutic relevance of this family, which has begun to show promise in cancer clinical trials. Significance: Recent studies have outlined the immuno-oncologic ascendancy of coinhibitory receptors in the DNAM1 axis such as TIGIT and PVRIG and, to a lesser extent, CD96. Biological elucidation backed by ongoing clinical trials of single-agent therapy directed against TIGIT or PVRIG is beginning to provide the rationale for testing combination regimens of DNAM1 axis blockers in conjunction with anti–PD-1/PD-L1 agents.

Original languageEnglish (US)
Pages (from-to)1040-1051
Number of pages12
JournalCancer discovery
Issue number5
StatePublished - 2021

ASJC Scopus subject areas

  • Oncology


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