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ARID1A-Deficient Tumors Acquire Immunogenic Neoantigens during the Development of Resistance to Targeted Therapy

Masahiro Okada1, Satoru Yamasaki1, Hiroshi Nakazato1

  • 1Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Cancer Research
|September 4, 2024
PubMed

Insights

ARID1A deficiency combined with vemurafenib resistance generates immunogenic neoantigens, enhancing anti-PD-1 therapy in melanoma. These neoantigens can be targeted for vaccines against refractory tumors.

Area of Science:

  • Oncology
  • Immunology
  • Genetics

Background:

  • Neoantigen-based immunotherapy shows promise for intractable tumors, but identifying responsive patients requires robust biomarkers.
  • ARID1A mutations influence tumor immunogenicity, yet their link to immunotherapy response is inconsistent.
  • Targeted therapy resistance can alter tumor characteristics, impacting treatment efficacy.

Purpose of the Study:

  • To investigate the role of ARID1A status in predicting immunotherapeutic responses in targeted therapy-resistant cancers.
  • To explore the generation and therapeutic potential of neoantigens arising during targeted therapy resistance.
  • To evaluate the efficacy of anti-PD-1 antibody treatment in ARID1A-deficient versus ARID1A-intact tumors with acquired resistance.

Main Methods:

  • Developed vemurafenib-resistant mouse and human BRAFV600E melanoma models with and without ARID1A expression.
  • Administered anti-PD-1 antibody treatment to assess antitumor immune responses.
  • Analyzed neoantigen expression and immunogenicity in ARID1A-deficient and ARID1A-intact tumors.
  • Validated neoantigen-specific T-cell receptor responses in experimental human melanoma cells.

Main Results:

  • Anti-PD-1 therapy enhanced antitumor immunity in vemurafenib-resistant ARID1A-deficient tumors, but not in ARID1A-intact or sensitive tumors.
  • Vemurafenib resistance led to accumulated somatic mutations and high neoantigen expression in ARID1A-deficient tumors, increasing immunogenicity.
  • Newly generated neoantigens were identified as potential targets for immunotherapy vaccines.
  • Targeted therapy resistance-specific neoantigens in ARID1A-deficient melanoma cells elicited T-cell receptor responses.

Conclusions:

  • ARID1A status combined with acquired resistance to targeted therapy can serve as predictive biomarkers for immunotherapy response.
  • Neoantigens emerging during targeted therapy resistance offer promising therapeutic targets for refractory tumors.
  • Chemotherapy resistance can induce immunogenic neoantigens in ARID1A-deficient tumors, improving sensitivity to immune checkpoint blockade and vaccine development.

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