Abstract 173P
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.
Resources from the same session
100P - Phase II trial of tislelizumab plus bevacizumab and chemotherapy as the first-line therapy for persistent, recurrent, or metastatic cervical cancer: updated efficacy and safety results
Presenter: Jianqing Zhu
Session: Poster Display
101P - Progression-Free Survival is an acceptable surrogate endpoint for chemo-immunotherapy combinations in Cervical Carcinoma, an EORTC Young GCG study
Presenter: Ramon Yarza
Session: Poster Display
102P - Interim safety analysis of a phase 2 trial of cisplatin-sensitized radiation therapy and pembrolizumab for unresectable vulvar cancer
Presenter: Oladapo Yeku
Session: Poster Display
103P - Long-term survivorship rates among previously treated patients with advanced renal cell carcinoma (aRCC) achieving objective response with nivolumab
Presenter: Saby George
Session: Poster Display
105P - Preliminary efficacy and safety results from ‘ReBirth’, a phase II study of risk-based bladder-sparing therapy for MIBC.
Presenter: Yijun Shen
Session: Poster Display
106P - Treatment Sequencing in PD-L1-Positive Recurrent/Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC): Exploratory Analysis of the Phase 3 KEYNOTE-048 Study
Presenter: Amanda Psyrri
Session: Poster Display
108P - Real-world (RW) effectiveness and safety of adjuvant nivolumab (NIVO) in patients (pts) with melanoma in Belgium and Luxembourg: PRESERV MEL
Presenter: Bart Neyns
Session: Poster Display
109P - Prognosis of patients with metastatic melanoma with initial stable disease during treatment with anti-PD-1 monotherapy
Presenter: Inge Noringriis
Session: Poster Display
110P - Outcomes of CUPem: A prospective Phase II multicentre clinical Trial of Pembrolizumab in patients with pre-treated Cancer of Unknown Primary
Presenter: Harpreet Wasan
Session: Poster Display