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Sensitization of ovarian tumor to immune checkpoint blockade by boosting senescence-associated secretory phenotype

Xue Hao1, Bo Zhao1, Wei Zhou1

  • 1Immunology, Metastasis and Microenvironment Program, The Wistar Institute, Philadelphia, PA 19104, USA.

Iscience
|January 25, 2021
PubMed

Insights

Boosting senescent cells with irinotecan enhances their tumor-sensitizing effects for immune checkpoint blockade (ICB) therapy. Adoptive transfer of these boosted cells shows promise in overcoming resistance, particularly in ovarian cancer.

Area of Science:

  • Oncology
  • Immunotherapy
  • Cellular Senescence

Background:

  • Intrinsic resistance to immune checkpoint blockade (ICB) presents a significant clinical hurdle, especially in ovarian cancer.
  • Therapy-induced senescence-associated secretory phenotype (SASP) has emerged as a potential mechanism to overcome ICB resistance.

Purpose of the Study:

  • To investigate whether boosting therapy-induced senescent cells enhances their ability to sensitize tumors to ICB.
  • To explore the role of Topoisomerase 1 (TOP1) inhibitors in modulating SASP and its impact on ICB efficacy.

Main Methods:

  • Enhancement of cisplatin-induced SASP using TOP1 inhibitors (irinotecan) in therapy-induced senescent cells.
  • Adoptive transfer of SASP-boosted senescent cells into immunocompetent mice with established ovarian tumors.
  • Assessment of tumor sensitization to anti-PD-1 antibody therapy and evaluation of survival outcomes.

Main Results:

  • Intraperitoneal transfer of SASP-boosted senescent cells, combined with irinotecan, sensitized ovarian tumors to anti-PD-1 antibody therapy.
  • This approach significantly improved survival in tumor-bearing mice.
  • Tumor infiltration by transferred senescent cells and increased presence of activated CD8+ T cells and dendritic cells were observed.

Conclusions:

  • Adoptive transfer of SASP-boosted therapy-induced senescent cells is a viable strategy to overcome ICB resistance.
  • This approach holds potential as a novel therapeutic avenue for treating ICB-resistant cancers like ovarian cancer.
Keywords:
CancerImmunologyMolecular Biology

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