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PD-1 Blockade Combined with Heated Intraperitoneal Chemotherapy Improves Outcome in Experimental Peritoneal Metastases from Colonic Origin in a Murine Model

  • Peritoneal Surface Malignancy
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Heated intraperitoneal chemotherapy (HIPEC) was shown to induce immunogenicity of peritoneal metastases from colorectal cancer (PM-CRC) by induction of immunogenic cell death. We aimed to explore whether the addition of a checkpoint inhibitor would augment the effect of HIPEC in an experimental murine model of PM-CRC.

Methods

PM-CRC was established in C57BL mice by intraperitoneal inoculation of MC38 colon cancer cells. HIPEC was administered using the closed technique with mitomycin C (MMC). Clinical and immunological parameters were compared between animals treated with HIPEC alone and those treated with HIPEC + anti-programmed death receptor-1 (aPD-1).

Results

MMC-based HIPEC increased the overall survival of animals compared with sham-treated animals (22.8; 95% confidence interval [CI] 21.14–24.53 vs. 18.9 days; 95% CI 17.6–20.3, p < 0.001). The extent of peritoneal disease as measured by the modified peritoneal carcinomatosis index was also reduced by HIPEC. This clinical benefit was accompanied by increased infiltration of CD8+, CD68+, and CD20+ cells into tumor metastases in HIPEC-treated animals compared with sham-treated animals. We identified heat shock protein (HSP) 90 as a potential immunogenic cell death protein whose expression is increased under HIPEC conditions (fold change: 2.37 ± 1.5 vs. 1 without HIPEC, p < 0.05). Combined HIPEC + PD-1 treatment ameliorated survival compared with HIPEC alone and sham treatment (24.66; 95% CI 20.13–29.2 vs. 19; 95% CI 15.85–22.14 and 14.33 days; 95% CI 9.6–19.04, respectively; p = 0.008). This clinical effect was accompanied by increased CD8+ tumor infiltration.

Conclusions

HIPEC induced the expression of immunogenic cell death signals that can support an anti-tumor immune response. This response can be further exploited by a checkpoint inhibitor.

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Author notes

  1. Ravit Geva and Gilad Alon have contributed equally to this work.

Authors and Affiliations

  1. Institute of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Ravit Geva MD & Sharon Peles-Avraham MD

  2. Department of Surgery A, Peritoneal Surface Malignancy and Melanoma Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Gilad Alon MD, Shoshi Bar-David MSc, Nadav Nevo MD, Guy Lahat MD & Eran Nizri MD, PhD

  3. Laboratory of Surgical Oncology, Division of Surgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Gilad Alon MD, Shoshi Bar-David MSc, Nadav Nevo MD, Guy Lahat MD & Eran Nizri MD, PhD

  4. Department of Surgery, Assaf Harofeh Medical Center, Zerifin, Israel

    Maya Nathanson MD

  5. Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Asaf Aizic MD

  6. Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ravit Geva MD, Sharon Peles-Avraham MD, Guy Lahat MD & Eran Nizri MD, PhD

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  1. Ravit Geva MD
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Correspondence to Eran Nizri MD, PhD.

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Disclosures

Ravit Geva has received honoraria (self) from Roche, MSD, Merck, Medison, Janssen, Pfizer, and BMS, and advisory/consultancy fees from AstraZeneca, BOL Pharma, Roche, Ranium, JNJ, Bayer, and MSD; holds a leadership role with Pyxis (medical lead); has shareholder/stockholder/stock options with Pyxis (options); and has received travel/accommodation expenses from Takeda and Medison. Gilad Alon, Maya Nathanson, Shoshi Bar-David, Nadav Nevo, Asaf Aizic, Sharon Peles-Avraham, Guy Lahat and Eran Nizri have no disclosures to declare.

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Geva, R., Alon, G., Nathanson, M. et al. PD-1 Blockade Combined with Heated Intraperitoneal Chemotherapy Improves Outcome in Experimental Peritoneal Metastases from Colonic Origin in a Murine Model. Ann Surg Oncol 30, 2657–2663 (2023). https://doi.org/10.1245/s10434-022-13025-7

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