Bahar Saberzadeh-Ardestani, Zhenglong Liu, Mariam I Stein, Will A Sherman, Christy E Trussoni, Charles W Abbott, Dongyao Yan, Skyler Smith, Kandavel Shanmugam, Rondell P Graham, Alos Diallo, Joshua J Levy, Tamas Ordog, Frank A Sinicrope
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引用次数: 0
Abstract
Purpose: Digital proteomic profiling was performed to identify spatial context in relationship to patient response and survival after anti-PD-1 therapy in metastatic colorectal cancer (CRC).
Experimental design: Primary CRCs with deficient mismatch repair (d-MMR) from patients treated with anti-PD-1 antibodies were analyzed (N=30) using Digital Spatial Profiling (GeoMx® nCounter). At the invasive margin, 71 proteins were profiled in 10 regions of interest /slide that were segmented into 3 compartments labeled with pan-cytokeratin (PanCK; epithelia), CD45 (stromal cells) and SYTO13 (nuclei). In an independent cohort (n=13), DSP data and single cell transcriptomic data were analyzed. Differential protein abundance, after Benjamini-Hochberg correction, was examined by response and progression-free survival (PFS) using multivariable Cox regression.
Results: Protein abundance varied significantly between epithelial and stromal compartments. Nonresponders (NR) to anti-PD-1 showed higher fibronectin and smooth muscle actin (SMA) abundance in the epithelial compartment that were associated with significantly shorter PFS (HRadj: 6.49 and 4.52, respectively; p < 0.05). In CD45+ stroma, increased expression of proteins related to T-cells (CD3, CD4), NK cells (CD56), antigen presentation (CD40), immune activation (CD27, ICOS), and apoptosis (GZMA) were found in responders (vs NR) to anti-PD-1; each marker was significantly associated with longer patient PFS (0.02
Conclusions: Spatially resolved protein profiles within microenvironments of d-MMR CRCs can influence patient response and survival after anti-PD-1 highlighting their potential clinical significance.
期刊介绍：
Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.
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