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405 Impact of hyperthermic intraperitoneal chemotherapy (HIPEC) on tumor microenvironment (TME) in ovarian cancer – a subanalysis from a Phase I clinical trial
  1. T Dellinger1,
  2. T He1,
  3. P Lee1,
  4. W Guo1,
  5. H Cho1,
  6. X Wu1,
  7. W Liang2,
  8. D Schmolze1,
  9. M Razavi1,
  10. N Ruel1,
  11. E Han1,
  12. M Wakabayashi1,
  13. S Lee1,
  14. WC Lin1,
  15. M Kebria1,
  16. A Hakim1,
  17. M Cristea1,
  18. D Stewart1,
  19. E Wang1,
  20. M Raoof1,
  21. B Lee3 and
  22. L Rodriguez-Rodriguez1
  1. 1City of Hope National Medical Center, USA
  2. 2TGen, USA
  3. 3Stanford, USA


Background Immunogenic cell death has been suggested as a mechanism for HIPEC, through the release of heat shock proteins, and resulting in activation of tumor-specific T cells.

Methods This is a subgroup analysis of a Phase I trial using HIPEC with cisplatin 75 mg/m2 at time of optimal cytoreduction. Metastatic tumors from nine ovarian cancer patients were collected intraoperatively before and after HIPEC. Differentially expressed genes and pathways of pre- and post-HIPEC tumors were analyzed via whole-transcriptome sequencing (WTS). Immunofluorescent (IF) staining and multispectral imaging were used to determine composition and PD-1 expression of CD8+ and conventional CD4+ tumor-infiltrating lymphocytes (TILs), using antibodies against CD8, FOXP3, PD-1, and pancytokeratin (to distinguish cancer islands from stroma). Kaplan-Meier and log-rank tests compared the overall and progression free survivals (PFS) of patients with low versus high%PD-1 changes, based on dichotomization with respect to the median%PD-1 change.

Results Heatshock proteins comprised the top differentially upregulated genes in HIPEC-treated tumors. Gene set enrichment analysis revealed significant upregulation of immune pathways, including antigen processing/presentation. IF staining demonstrated increased%PD-1 in cancer islands of CD8+ and CD4+ TILs after HIPEC. In stroma, the largest%PD-1 change occurs in an exceptional responder (PFS, OS 5 years), while the lowest%PD-1 change occurred in a poor responder. Kaplan-Meier curves demonstrate superior PFS in patients with high stromal PD-1 changes in TILs after HIPEC.

Abstract 405 Figure 1

PD-1 expression increases after HIPEC in cancer islands of CD4+ conventional T cells, and stromal PD-1 expression changes correlate with survival. A.%PD-1 expression in CD4+ T cell cancer islands, before and after HIPEC.%PD-1 expression is significantly increased after HIPEC. B.%PD-1 expression changes in individual patients after HIPEC (in stroma). Pt 2 is an exceptional responder with PFS and OS of 5 years, while Pt 1 is a poor responder. C and D. Kaplan-Meier curves of Progression-free survival (PFS) and Overall Survival (OS) in patients with high (pink) vs low (blue) HIPEC-induced%PD-1 expression changes in CD4+ T cell stroma (based on median%PD-1 expression threshold).

Conclusions Increased PD-1 expression after HIPEC suggests early HIPEC-induced T cell activation, and is associated with improved survival, implicating a potential future role for PD-1 inhibitors following HIPEC in ovarian cancer.

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