Treatment of colorectal peritoneal metastases with oxaliplatin induces biomarkers predicting response to immune checkpoint blockade

Alexander Constantinides; Nico Lansu; Peter Mosen; Paulien Rauwerdink; Esther Strating; Franziska Völlmy; Maaike Nederend; Jeanette H W Leusen; Koen Rovers; Emma Wassenaar; Robin Lurvink; Maarten Altelaar; Simon Nienhuijs; Rene Wiezer; Inne H M Borel Rinkes; Djamila Boerma; Geert J P L Kops; Ignace de Hingh; Onno Kranenburg

doi:10.1016/j.tranon.2025.102464

Treatment of colorectal peritoneal metastases with oxaliplatin induces biomarkers predicting response to immune checkpoint blockade

Alexander Constantinides
, Nico Lansu
, Peter Mosen
, Paulien Rauwerdink
, Esther Strating
, Franziska Völlmy
, Maaike Nederend
, Jeanette H W Leusen
, Koen Rovers
, Emma Wassenaar
, Robin Lurvink
, Maarten Altelaar
, Simon Nienhuijs
, Rene Wiezer
, Inne H M Borel Rinkes
, Djamila Boerma
, Geert J P L Kops
, Ignace de Hingh^*
, Onno Kranenburg^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: Colorectal cancer (CRC) patients with inoperable peritoneal metastases (PM) have a dismal prognosis with limited treatment options. Local treatment of CRC-PM with oxaliplatin is commonly applied, but biomarkers steering patient selection, or informing potentially effective combination therapies are lacking. A novel potentially effective treatment strategy is Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in which CRC-PM are exposed to cyclic treatment with high concentrations of locally applied oxaliplatin. However, it is unclear whether and how CRC-PM respond to PIPAC.

METHODS: Here, we generated a biobank from 20 patients receiving PIPAC with oxaliplatin for CRC-PM. The biobank contains biopsies from 3 PM per patient, repeatedly sampled prior to each treatment cycle, and ascites. Anti-tumor effects were analyzed by shallow single-cell karyotype sequencing (sc-karyoSeq). RNA-sequencing and proteomics were performed to assess changes in gene and protein expression. Immunohistochemistry was performed to assess treatment-induced changes in tissue histology. Ascites was used to assess immunoglobulin content and reactivity.

RESULTS: PIPAC reduced genomic heterogeneity and aneuploidy scores among PIPAC-surviving tumor cells. Furthermore, PIPAC reduced immunosuppressive signals (hypoxia, interleukin-10, transforming growth factor β), and induced an influx of B and T lymphocytes, which organized into metastasis-associated Tertiary Lymphoid Structures (TLS). TLS are biomarkers predicting response to Immune-Checkpoint Inhibitors (ICIs). The T cells residing in PIPAC-induced TLS expressed high levels of the checkpoints PD-1, TIGIT and EBI3. PIPAC also caused the generation of plasma cells producing tumor-reactive antibodies.

CONCLUSION: PIPAC shows modest anti-tumor activity and induces immune parameters predicting response to ICIs. Patients with inoperable CRC-PM may therefore benefit from PIPAC in combination with ICIs.

Original language	English
Article number	102464
Number of pages	11
Journal	Translational Oncology
Volume	59
Early online date	1 Jul 2025
DOIs	https://doi.org/10.1016/j.tranon.2025.102464
Publication status	Published - Sept 2025

Bibliographical note

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

CRC
Colorectal
Heterogeneity
Karyotype
Oxaliplatin
PIPAC
Peritoneal metastasis
Reverse translation
Tertiary lymphoid structure

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10.1016/j.tranon.2025.102464Licence: CC BY

Treatment of colorectal peritoneal metastases with oxaliplatin induces biomarkers predicting response to immune checkpoint blockadeFinal published version, 14.3 MBLicence: CC BY

Cite this

Constantinides, A., Lansu, N., Mosen, P., Rauwerdink, P., Strating, E., Völlmy, F., Nederend, M., Leusen, J. H. W., Rovers, K., Wassenaar, E., Lurvink, R., Altelaar, M., Nienhuijs, S., Wiezer, R., Borel Rinkes, I. H. M., Boerma, D., Kops, G. J. P. L., de Hingh, I., & Kranenburg, O. (2025). Treatment of colorectal peritoneal metastases with oxaliplatin induces biomarkers predicting response to immune checkpoint blockade. Translational Oncology, 59, Article 102464. https://doi.org/10.1016/j.tranon.2025.102464

@article{e70a8e3128014f7a81b22fddcf461b43,

title = "Treatment of colorectal peritoneal metastases with oxaliplatin induces biomarkers predicting response to immune checkpoint blockade",

abstract = "BACKGROUND: Colorectal cancer (CRC) patients with inoperable peritoneal metastases (PM) have a dismal prognosis with limited treatment options. Local treatment of CRC-PM with oxaliplatin is commonly applied, but biomarkers steering patient selection, or informing potentially effective combination therapies are lacking. A novel potentially effective treatment strategy is Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in which CRC-PM are exposed to cyclic treatment with high concentrations of locally applied oxaliplatin. However, it is unclear whether and how CRC-PM respond to PIPAC.METHODS: Here, we generated a biobank from 20 patients receiving PIPAC with oxaliplatin for CRC-PM. The biobank contains biopsies from 3 PM per patient, repeatedly sampled prior to each treatment cycle, and ascites. Anti-tumor effects were analyzed by shallow single-cell karyotype sequencing (sc-karyoSeq). RNA-sequencing and proteomics were performed to assess changes in gene and protein expression. Immunohistochemistry was performed to assess treatment-induced changes in tissue histology. Ascites was used to assess immunoglobulin content and reactivity.RESULTS: PIPAC reduced genomic heterogeneity and aneuploidy scores among PIPAC-surviving tumor cells. Furthermore, PIPAC reduced immunosuppressive signals (hypoxia, interleukin-10, transforming growth factor β), and induced an influx of B and T lymphocytes, which organized into metastasis-associated Tertiary Lymphoid Structures (TLS). TLS are biomarkers predicting response to Immune-Checkpoint Inhibitors (ICIs). The T cells residing in PIPAC-induced TLS expressed high levels of the checkpoints PD-1, TIGIT and EBI3. PIPAC also caused the generation of plasma cells producing tumor-reactive antibodies.CONCLUSION: PIPAC shows modest anti-tumor activity and induces immune parameters predicting response to ICIs. Patients with inoperable CRC-PM may therefore benefit from PIPAC in combination with ICIs.",

keywords = "CRC, Colorectal, Heterogeneity, Karyotype, Oxaliplatin, PIPAC, Peritoneal metastasis, Reverse translation, Tertiary lymphoid structure",

author = "Alexander Constantinides and Nico Lansu and Peter Mosen and Paulien Rauwerdink and Esther Strating and Franziska V{\"o}llmy and Maaike Nederend and Leusen, \{Jeanette H W\} and Koen Rovers and Emma Wassenaar and Robin Lurvink and Maarten Altelaar and Simon Nienhuijs and Rene Wiezer and \{Borel Rinkes\}, \{Inne H M\} and Djamila Boerma and Kops, \{Geert J P L\} and \{de Hingh\}, Ignace and Onno Kranenburg",

note = "Copyright {\textcopyright} 2025. Published by Elsevier Inc.",

year = "2025",

month = sep,

doi = "10.1016/j.tranon.2025.102464",

language = "English",

volume = "59",

journal = "Translational Oncology",

issn = "1936-5233",

publisher = "Neoplasia Press, Inc.",

}

Constantinides, A, Lansu, N, Mosen, P, Rauwerdink, P, Strating, E, Völlmy, F, Nederend, M, Leusen, JHW, Rovers, K, Wassenaar, E, Lurvink, R, Altelaar, M, Nienhuijs, S, Wiezer, R, Borel Rinkes, IHM, Boerma, D, Kops, GJPL, de Hingh, I & Kranenburg, O 2025, 'Treatment of colorectal peritoneal metastases with oxaliplatin induces biomarkers predicting response to immune checkpoint blockade', Translational Oncology, vol. 59, 102464. https://doi.org/10.1016/j.tranon.2025.102464

TY - JOUR

T1 - Treatment of colorectal peritoneal metastases with oxaliplatin induces biomarkers predicting response to immune checkpoint blockade

AU - Constantinides, Alexander

AU - Lansu, Nico

AU - Mosen, Peter

AU - Rauwerdink, Paulien

AU - Strating, Esther

AU - Völlmy, Franziska

AU - Nederend, Maaike

AU - Leusen, Jeanette H W

AU - Rovers, Koen

AU - Wassenaar, Emma

AU - Lurvink, Robin

AU - Altelaar, Maarten

AU - Nienhuijs, Simon

AU - Wiezer, Rene

AU - Borel Rinkes, Inne H M

AU - Boerma, Djamila

AU - Kops, Geert J P L

AU - de Hingh, Ignace

AU - Kranenburg, Onno

PY - 2025/9

Y1 - 2025/9

N2 - BACKGROUND: Colorectal cancer (CRC) patients with inoperable peritoneal metastases (PM) have a dismal prognosis with limited treatment options. Local treatment of CRC-PM with oxaliplatin is commonly applied, but biomarkers steering patient selection, or informing potentially effective combination therapies are lacking. A novel potentially effective treatment strategy is Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in which CRC-PM are exposed to cyclic treatment with high concentrations of locally applied oxaliplatin. However, it is unclear whether and how CRC-PM respond to PIPAC.METHODS: Here, we generated a biobank from 20 patients receiving PIPAC with oxaliplatin for CRC-PM. The biobank contains biopsies from 3 PM per patient, repeatedly sampled prior to each treatment cycle, and ascites. Anti-tumor effects were analyzed by shallow single-cell karyotype sequencing (sc-karyoSeq). RNA-sequencing and proteomics were performed to assess changes in gene and protein expression. Immunohistochemistry was performed to assess treatment-induced changes in tissue histology. Ascites was used to assess immunoglobulin content and reactivity.RESULTS: PIPAC reduced genomic heterogeneity and aneuploidy scores among PIPAC-surviving tumor cells. Furthermore, PIPAC reduced immunosuppressive signals (hypoxia, interleukin-10, transforming growth factor β), and induced an influx of B and T lymphocytes, which organized into metastasis-associated Tertiary Lymphoid Structures (TLS). TLS are biomarkers predicting response to Immune-Checkpoint Inhibitors (ICIs). The T cells residing in PIPAC-induced TLS expressed high levels of the checkpoints PD-1, TIGIT and EBI3. PIPAC also caused the generation of plasma cells producing tumor-reactive antibodies.CONCLUSION: PIPAC shows modest anti-tumor activity and induces immune parameters predicting response to ICIs. Patients with inoperable CRC-PM may therefore benefit from PIPAC in combination with ICIs.

AB - BACKGROUND: Colorectal cancer (CRC) patients with inoperable peritoneal metastases (PM) have a dismal prognosis with limited treatment options. Local treatment of CRC-PM with oxaliplatin is commonly applied, but biomarkers steering patient selection, or informing potentially effective combination therapies are lacking. A novel potentially effective treatment strategy is Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in which CRC-PM are exposed to cyclic treatment with high concentrations of locally applied oxaliplatin. However, it is unclear whether and how CRC-PM respond to PIPAC.METHODS: Here, we generated a biobank from 20 patients receiving PIPAC with oxaliplatin for CRC-PM. The biobank contains biopsies from 3 PM per patient, repeatedly sampled prior to each treatment cycle, and ascites. Anti-tumor effects were analyzed by shallow single-cell karyotype sequencing (sc-karyoSeq). RNA-sequencing and proteomics were performed to assess changes in gene and protein expression. Immunohistochemistry was performed to assess treatment-induced changes in tissue histology. Ascites was used to assess immunoglobulin content and reactivity.RESULTS: PIPAC reduced genomic heterogeneity and aneuploidy scores among PIPAC-surviving tumor cells. Furthermore, PIPAC reduced immunosuppressive signals (hypoxia, interleukin-10, transforming growth factor β), and induced an influx of B and T lymphocytes, which organized into metastasis-associated Tertiary Lymphoid Structures (TLS). TLS are biomarkers predicting response to Immune-Checkpoint Inhibitors (ICIs). The T cells residing in PIPAC-induced TLS expressed high levels of the checkpoints PD-1, TIGIT and EBI3. PIPAC also caused the generation of plasma cells producing tumor-reactive antibodies.CONCLUSION: PIPAC shows modest anti-tumor activity and induces immune parameters predicting response to ICIs. Patients with inoperable CRC-PM may therefore benefit from PIPAC in combination with ICIs.

KW - CRC

KW - Colorectal

KW - Heterogeneity

KW - Karyotype

KW - Oxaliplatin

KW - PIPAC

KW - Peritoneal metastasis

KW - Reverse translation

KW - Tertiary lymphoid structure

U2 - 10.1016/j.tranon.2025.102464

DO - 10.1016/j.tranon.2025.102464

M3 - Article

C2 - 40602034

SN - 1936-5233

VL - 59

JO - Translational Oncology

JF - Translational Oncology

M1 - 102464

ER -

Treatment of colorectal peritoneal metastases with oxaliplatin induces biomarkers predicting response to immune checkpoint blockade

Abstract

Bibliographical note

UN SDGs

Keywords

Access to Document

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Cite this