論文

2022年9月1日

Combination of a novel heat shock protein 90-targeted photodynamic therapy with PD-1/PD-L1 blockade induces potent systemic antitumor efficacy and abscopal effect against breast cancers.

Journal for immunotherapy of cancer
  • Kaneko K
  • Chaitanya Acharya
  • Hiroshi Nagata
  • Yang X
  • Zachary Hartman
  • Hobeika A
  • Hughes PF
  • Haystead TAJ
  • Morse MA
  • Herbert Kim Lyerly
  • Takuya Osada
  • 全て表示

記述言語
掲載種別
研究論文(学術雑誌)
DOI
10.1136/jitc-2022-004793

<h4>Background</h4>We previously demonstrated potent antitumor activity against human breast cancer xenografts using photodynamic therapy (PDT) targeting a novel tumor-specific photosensitizer (HS201), which binds heat shock protein 90 (HS201-PDT). However, induction of systemic antitumor immunity by HS201-PDT alone or by the combination strategy with immune checkpoint blockade has yet to be determined.<h4>Methods</h4>Using unilateral and bilateral implantation models of syngeneic breast tumors (E0771, MM3MG-HER2, and JC-HER3) in mice, we assessed whether HS201-PDT could induce local and systemic antitumor immunity. In an attempt to achieve a stronger abscopal effect for distant tumors, the combination strategy with anti-PD-L1 antibody was tested. Tumor-infiltrating leukocytes were analyzed by single cell RNA-sequencing and receptor-ligand interactome analysis to characterize in more detailed the mechanisms of action of the treatment and key signaling pathways involved.<h4>Results</h4>HS201-PDT demonstrated greater tumor control and survival in immune competent mice than in immunocompromised mice, suggesting the role of induced antitumor immunity; however, survival was modest and an abscopal effect on distant implanted tumor was weak. A combination of HS201-PDT with anti-PD-L1 antibody demonstrated the greatest antigen-specific immune response, tumor growth suppression, prolonged mouse survival time and abscopal effect. The most significant increase of intratumoral, activated CD8+T cells and decrease of exhausted CD8+T cells occurred following combination treatment compared with HS201-PDT monotherapy. Receptor-ligand interactome analysis showed marked enhancement of several pathways, such as CXCL, GALECTIN, GITRL, PECAM1 and NOTCH, associated with CD8+T cell activation in the combination group. Notably, the expression of the CXCR3 gene signature was the highest in the combination group, possibly explaining the enhanced tumor infiltration by T cells.<h4>Conclusions</h4>The increased antitumor activity and upregulated CXCR3 gene signature induced by the combination of anti-PD-L1 antibody with HS201-PDT warrants the clinical testing of HS201-PDT combined with PD-1/PD-L1 blockade in patients with breast cancer, and the use of the CXCR3 gene signature as a biomarker.

リンク情報
DOI
https://doi.org/10.1136/jitc-2022-004793
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/36171008
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9528636
URL
https://europepmc.org/articles/PMC9528636
ID情報
  • DOI : 10.1136/jitc-2022-004793
  • ORCIDのPut Code : 136783448
  • PubMed ID : 36171008
  • PubMed Central 記事ID : PMC9528636

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