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

Overview

Journal Ann Surg Oncol

Publisher Springer

Specialty Oncology

Date 2023 Jan 3

PMID 36595112

Authors

Ravit Geva

Gilad Alon

Maya Nathanson

Shoshi Bar-David

Nadav Nevo

Asaf Aizic

Sharon Peles-Avraham

Guy Lahat

Eran Nizri

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Quenet F, Elias D, Roca L, Goere D, Ghouti L, Pocard M . Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021; 22(2):256-266. DOI: 10.1016/S1470-2045(20)30599-4. View

van de Vlasakker V, Lurvink R, Cashin P, Ceelen W, Deraco M, Goere D . The impact of PRODIGE 7 on the current worldwide practice of CRS-HIPEC for colorectal peritoneal metastases: A web-based survey and 2021 statement by Peritoneal Surface Oncology Group International (PSOGI). Eur J Surg Oncol. 2021; 47(11):2888-2892. DOI: 10.1016/j.ejso.2021.05.023. View

Elias D, Gilly F, Boutitie F, Quenet F, Bereder J, Mansvelt B . Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study. J Clin Oncol. 2009; 28(1):63-8. DOI: 10.1200/JCO.2009.23.9285. View

Baratti D, Kusamura S, Pietrantonio F, Guaglio M, Niger M, Deraco M . Progress in treatments for colorectal cancer peritoneal metastases during the years 2010-2015. A systematic review. Crit Rev Oncol Hematol. 2016; 100:209-22. DOI: 10.1016/j.critrevonc.2016.01.017. View

Carlino M, Larkin J, Long G . Immune checkpoint inhibitors in melanoma. Lancet. 2021; 398(10304):1002-1014. DOI: 10.1016/S0140-6736(21)01206-X. View

Breakstone R . Colon cancer and immunotherapy-can we go beyond microsatellite instability?. Transl Gastroenterol Hepatol. 2021; 6:12. PMC: 7724178. DOI: 10.21037/tgh.2020.03.08. View

Andre T, Shiu K, Kim T, Jensen B, Jensen L, Punt C . Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020; 383(23):2207-2218. DOI: 10.1056/NEJMoa2017699. View

Maby P, Bindea G, Mlecnik B, Galon J . License to kill: microsatellite instability and immune contexture. Oncoimmunology. 2021; 10(1):1905935. PMC: 8023238. DOI: 10.1080/2162402X.2021.1905935. View

Eng C, Kim T, Bendell J, Argiles G, Tebbutt N, Di Bartolomeo M . Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2019; 20(6):849-861. DOI: 10.1016/S1470-2045(19)30027-0. View

10.

Zhou J, Wang G, Chen Y, Wang H, Hua Y, Cai Z . Immunogenic cell death in cancer therapy: Present and emerging inducers. J Cell Mol Med. 2019; 23(8):4854-4865. PMC: 6653385. DOI: 10.1111/jcmm.14356. View

11.

Fucikova J, Kepp O, Kasikova L, Petroni G, Yamazaki T, Liu P . Detection of immunogenic cell death and its relevance for cancer therapy. Cell Death Dis. 2020; 11(11):1013. PMC: 7691519. DOI: 10.1038/s41419-020-03221-2. View

12.

Turaga K, Levine E, Barone R, Sticca R, Petrelli N, Lambert L . Consensus guidelines from The American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States. Ann Surg Oncol. 2013; 21(5):1501-5. DOI: 10.1245/s10434-013-3061-z. View

13.

Wei S, Anang N, Sharma R, Andrews M, Reuben A, Levine J . Combination anti-CTLA-4 plus anti-PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies. Proc Natl Acad Sci U S A. 2019; 116(45):22699-22709. PMC: 6842624. DOI: 10.1073/pnas.1821218116. View

14.

Jacquet P, Sugarbaker P . Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis. Cancer Treat Res. 1996; 82:359-74. DOI: 10.1007/978-1-4613-1247-5_23. View

15.

Nizri E, Sternbach N, Bar-David S, Ben-Yehuda A, Gerstenhaber F, Ofir T . T-Helper 1 Immune Response in Metastatic Lymph Nodes of Pancreatic Ductal Adenocarcinoma: A Marker For Prolonged Survival. Ann Surg Oncol. 2017; 25(2):475-481. DOI: 10.1245/s10434-017-6237-0. View

16.

Bankhead P, Loughrey M, Fernandez J, Dombrowski Y, McArt D, Dunne P . QuPath: Open source software for digital pathology image analysis. Sci Rep. 2017; 7(1):16878. PMC: 5715110. DOI: 10.1038/s41598-017-17204-5. View

17.

Helderman R, Loke D, Tanis P, Tuynman J, Ceelen W, de Hingh I . Preclinical In Vivo-Models to Investigate HIPEC; Current Methodologies and Challenges. Cancers (Basel). 2021; 13(14). PMC: 8303745. DOI: 10.3390/cancers13143430. View

18.

Lehmann K, Rickenbacher A, Jang J, Oberkofler C, Vonlanthen R, von Boehmer L . New insight into hyperthermic intraperitoneal chemotherapy: induction of oxidative stress dramatically enhanced tumor killing in in vitro and in vivo models. Ann Surg. 2012; 256(5):730-7. DOI: 10.1097/SLA.0b013e3182737517. View

19.

Zunino B, Rubio-Patino C, Villa E, Meynet O, Proics E, Cornille A . Hyperthermic intraperitoneal chemotherapy leads to an anticancer immune response via exposure of cell surface heat shock protein 90. Oncogene. 2015; 35(2):261-8. DOI: 10.1038/onc.2015.82. View

20.

Durgeau A, Virk Y, Corgnac S, Mami-Chouaib F . Recent Advances in Targeting CD8 T-Cell Immunity for More Effective Cancer Immunotherapy. Front Immunol. 2018; 9:14. PMC: 5786548. DOI: 10.3389/fimmu.2018.00014. View