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

Colorectal cancer patients with inoperable peritoneal metastases have a very poor prognosis with limited treatment options. Pressurized Intraperitoneal Chemotherapy with oxaliplatin (PIPAC-OX) is being evaluated as an alternative treatment strategy. We determined the genetic, cellular and molecular response of colorectal peritoneal metastases to PIPAC-OX. Single cell karyotype sequencing showed that PIPAC-OX reduced genomic heterogeneity and aneuploidy scores among PIPAC-OX-surviving tumor cells. RNA-sequencing, proteomics and immunohistochemistry further showed that PIPAC-OX reduced immunosuppressive signals (hypoxia, interleukin-10, transforming growth factor b), and induced an influx of B and T cells, 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-OX-induced TLS expressed high levels of the checkpoints PD-1, TIGIT and EBI3. PIPAC-OX also caused the generation of plasma cells producing tumor-reactive antibodies. We propose that patients with inoperable colorectal peritoneal metastases may benefit from PIPAC-OX in combination with ICIs.