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Overcoming acquired resistance to cancer immune checkpoint therapy: potential strategies based on molecular

Bin Wang1,2, Yin Han3, Yuyu Zhang1,4,5

  • 1Department of Radiation Oncology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China.

Cell & Bioscience
|June 29, 2023
PubMed

Insights

Acquired resistance to immune checkpoint inhibitors (ICIs) is a major challenge in cancer treatment. This review explores mechanisms like antigen presentation issues and microbiome changes, and discusses strategies to overcome ICI resistance for better patient outcomes.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Therapeutics

Background:

  • Immune checkpoint inhibitors (ICIs) targeting CTLA-4 and PD-1/PD-L1 have advanced cancer treatment, offering durable responses and improved survival for various malignancies.
  • Acquired resistance to ICIs after initial response is a significant obstacle, limiting long-term efficacy.
  • Understanding the mechanisms of acquired resistance is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To review the current understanding of mechanisms underlying acquired resistance to immune checkpoint inhibitors (ICIs).
  • To discuss potential therapeutic strategies aimed at reversing ICI resistance and improving clinical benefits for cancer patients.

Main Methods:

  • Literature review focusing on acquired resistance mechanisms to ICIs.
  • Analysis of factors contributing to resistance, including antigen presentation, signaling pathways, immune microenvironment, epigenetic modifications, and gut microbiome dysbiosis.
  • Exploration of therapeutic strategies to overcome ICI resistance.

Main Results:

  • Key mechanisms of acquired resistance include lack of neoantigens, impaired antigen presentation, mutations in IFN-γ/JAK signaling, activation of alternative immune checkpoints, an immunosuppressive tumor microenvironment, epigenetic alterations, and gut microbiome dysbiosis.
  • These mechanisms collectively contribute to the loss of anti-tumor T cell immunity.
  • Potential strategies to reverse resistance are discussed based on these identified mechanisms.

Conclusions:

  • Acquired resistance to ICIs is multifactorial, involving complex interactions within the tumor and its microenvironment.
  • Targeting these resistance mechanisms offers promising avenues for enhancing ICI efficacy.
  • Further research into overcoming ICI resistance is essential for improving outcomes in cancer patients.
Keywords:
Acquired resistanceCombination therapyImmune checkpoint inhibitorsMechanismsTumor microenvironment

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