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Therapeutic Targeting of Checkpoint Receptors within the DNAM1 Axis

Zoya Alteber1, Maya F Kotturi2, Sarah Whelan2

  • 1Compugen Ltd, Holon, Israel.

Cancer Discovery
|March 10, 2021
PubMed

Insights

Cancer immunotherapies targeting CTLA4/PD-1 pathways show promise but resistance occurs. The DNAM1 axis, including TIGIT and PVRIG, offers new therapeutic targets for overcoming resistance and improving cancer treatment outcomes.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Cancer immunotherapy using antibodies against CTLA4 and PD-1 pathways has led to significant advancements in treating various cancers.
  • Despite initial responses, many patients experience relapse due to primary and adaptive resistance mechanisms.
  • Investigating alternative immunomodulatory pathways is crucial for overcoming resistance to current immunotherapies.

Purpose of the Study:

  • To review the basic biology of the DNAM1 axis, including its components TIGIT, PVRIG, and CD96, and their ligands.
  • To explore the therapeutic relevance and potential of targeting the DNAM1 axis in cancer treatment.
  • To provide a rationale for combining DNAM1 axis blockers with existing anti-PD-1/PD-L1 therapies.

Main Methods:

  • Literature review of basic biology and recent clinical trial data.
  • Analysis of the role of DNAM1 axis coinhibitory receptors in cancer immunity.
  • Synthesis of findings to support combination therapy strategies.

Main Results:

  • The DNAM1 axis, comprising TIGIT, PVRIG, and CD96, is a key regulator of innate and adaptive immunity.
  • These coinhibitory receptors, particularly TIGIT and PVRIG, are emerging as significant targets in immuno-oncology.
  • Early clinical trials show promise for single-agent therapies targeting TIGIT or PVRIG.

Conclusions:

  • The DNAM1 axis represents a promising avenue for novel cancer immunotherapies.
  • Combination strategies involving DNAM1 axis blockers and anti-PD-1/PD-L1 agents are warranted to enhance durable responses and overcome resistance.

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