173P - Depleting resident peritoneal macrophages is an effective treatment for peritoneal metastasized colorectal cancer

Background

Peritoneal metastases (PM) have an extremely poor survival irrespective of the primary cancer type. The reason for poor survival is the lack of therapies and the poor response to systemic treatment. We hypothesize that the peritoneal immune system (PerIS) underlies therapy resistance. The aim of this study was to characterize the PerIS in healthy individuals and patients with PM-colorectal cancer (PM-CRC), to identify novel treatment targets and combat peritoneal carcinomatosis.

Methods

Cellular indexing of transcriptomes and epitopes sequencing (CITE-seq) and single cell RNA-sequencing (scRNA-seq) was used to define the PerIS in peritoneal flushes (PF) from healthy individuals (n=5) and PM-CRC patients (n=13) undergoing elective surgery. The PerIS was compared to peripheral blood mononuclear cells (PBMCs), primary colon tissue and liver tissue. In PM-CRC mouse models (i.p. injection mouse CRC cell line CT26), macrophages were depleted using i.p. anti-CSF1R, with or without anti-PD1 treatment, or vehicle control. Primary outcome was survival and secondary outcomes were the modified peritoneal carcinomatosis index (mPCI) and ascites score.

Results

The healthy PerIS is characterized by immunosuppressive resident C1QA⁺VSIG4⁺ macrophages. The PerIS contains significantly more macrophages (mean: 28.0%) compared to colon (mean: 3.2%) and liver (mean: 1.6%). In PM-CRC, these macrophages become even more immunosuppressive with higher gene expression of IL10 and VEGFA and reduced expression of antigen presenting molecules. Moreover, protein levels of cytokines like IL10 (p=0.0006) and VEGFA (p=0.0003) are increased in PF of PM-CRC patients compared to healthy individuals and correlate to the PCI. In PM-CRC, C1Q⁺SPP1⁺ infiltrating macrophages were amongst the most abundant immune cells and contributed to immunosuppression. Intriguingly, mice studies demonstrated that anti-CSF1R/anti-PD1 combination therapy effectively reduced mPCI, ascites score and improved survival compared to vehicle control (p=0.0001), anti-CSF1R (p=0.005) and anti-PD1 (p=0.039).

Conclusions

Peritoneal resident macrophages define the peritoneal immunosuppressive niche and are a promising therapeutic target for PM-CRC.

Legal entity responsible for the study

Amsterdam UMC.

Funding

NWO VENI, KWF YIG, TKI grant and Amsterdam UMC PhD scholarship.

Disclosure

All authors have declared no conflicts of interest.