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.