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Histone Deacetylase Inhibition Sensitizes PD1 Blockade-Resistant B-cell Lymphomas

Xiaoguang Wang1, Brittany C Waschke1, Rachel A Woolaver1

  • 1Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.

Cancer Immunology Research
|June 26, 2019
PubMed

Insights

Histone deacetylase inhibitors (HDACi) like OKI-179 can enhance PD1 blockade effectiveness in B-cell lymphomas. This combination therapy improves tumor immunogenicity, particularly in PD1-resistant cases.

Area of Science:

  • Immunology
  • Oncology
  • Pharmacology

Background:

  • PD1 blockade is a cancer immunotherapy with limited efficacy in B-cell lymphomas.
  • Tumor resistance to PD1 blockade is often associated with immunosuppressive features, including reduced MHC expression and T-cell exhaustion.

Purpose of the Study:

  • To investigate the potential of an isoform-selective histone deacetylase inhibitor (HDACi), OKI-179, in overcoming PD1 blockade resistance in B-cell lymphomas.
  • To elucidate the mechanisms by which HDACi influences tumor immunogenicity and anti-PD1 therapy response.

Main Methods:

  • Utilized two mouse B-cell lymphoma models, including the G1XP lymphoma, which exhibits immunosuppressive characteristics similar to human B-cell lymphomas.
  • Administered OKI-179 (HDACi) in combination with anti-PD1 therapy to assess treatment efficacy and tumor growth inhibition.
  • Analyzed the role of tumor-derived MHC class I and II expression in mediating sensitivity to single and combined treatments.

Main Results:

  • Combined treatment with OKI-179 and anti-PD1 significantly inhibited the growth of PD1-refractory B-cell lymphomas.
  • Treatment sensitivity was dependent on tumor-derived MHC class I and positively correlated with MHC class II expression levels.
  • Different HDACis demonstrated varied effects on tumors and T cells, and the same HDACi impacted HLA expression differently across human B-cell lymphoma subtypes.

Conclusions:

  • OKI-179 sensitizes B-cell lymphomas to PD1 blockade by enhancing tumor immunogenicity, offering a potential strategy to improve immunotherapy outcomes.
  • Optimal therapeutic strategies require personalized treatment designs and rational combinations based on prognostic biomarkers like MHCs and individual HDACi profiles.

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