Patient-derived colorectal microtumors predict response to anti-PD-1 therapy

Area of Science:

• Oncology
• Immunotherapy
• Cancer Research

Background:

• Colorectal cancer (CRC) remains a significant cause of cancer mortality.
• While anti-PD-1 therapy benefits microsatellite instability (MSI) CRC, most patients are microsatellite stable (MSS).
• A subset of MSS CRC with POLE mutations and high tumor mutational burden (TMB) shows unexpected responses to immunotherapy.

Purpose of the Study:

• To develop a novel 3D ex vivo immunotherapy model for predicting anti-PD-1 response in CRC.
• To investigate the potential of this model in identifying responders among MSS CRC patients with specific mutations.
• To guide personalized treatment strategies for CRC based on predictive biomarkers.

Main Methods:

• Established a 3D ex vivo co-culture system with patient-derived CRC microtumors and autologous peripheral blood mononuclear cells (PBMCs).
• Treated microtumors ex vivo with pembrolizumab (anti-PD-1 therapy).
• Assessed interferon-gamma (IFN-γ) secretion and T-cell infiltration as indicators of immune response.

Main Results:

• The 3D ex vivo model demonstrated heterogeneous but appreciable IFN-γ secretion and T-cell infiltration upon pembrolizumab treatment.
• A case study highlighted a POLE-mutated, ultrahigh TMB MSS CRC phenotype responding to PD-1 blockade.
• The model showed potential in reflecting treatment response in specific CRC subtypes.

Conclusions:

• The novel 3D ex vivo model can predict anti-PD-1 therapy response in CRC.
• This model may identify MSS CRC patients with POLE mutations and high TMB as potential responders.
• The model serves as a valuable tool for personalized treatment planning in CRC.