Original Article
Immune profiling of microsatellite instability-high and polymerase ε (POLE)-mutated metastatic colorectal tumors identifies predictors of response to anti-PD-1 therapy
Abstract
Background: Microsatellite instability-high (MSI-H) and polymerase ε (POLE)-mutated metastatic colorectal cancer (mCRC) represent hypermutated and ultramutated tumor phenotypes, respectively, that may predict benefit to checkpoint blockade [anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1)].
Methods: Immune profiling through multispectral fluorescent immunohistochemistry (IHC) using a multimarker staining panel was performed on pretreatment tumor specimens from a cohort of MSI-H or POLE mCRC patients treated with PD-1 blockade at our institution to identify candidate predictors of response to checkpoint inhibitors.
Results: From 4/2013 to 1/2017, a total of 237 mCRC patients with molecularly profiled tumors were screened. Five MSI-H and three POLE-mutated mCRC patients were treated with checkpoint inhibitors. Immune profiling identified higher CD8+ tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment (TME) of responders (CR or PR as best response) than nonresponders (SD or PD as best response). Responders had significantly higher densities of CD8+ PD-1+ TILs than nonresponders (P=0.0007). PD-L1 expression (P=0.73), CD4+ T-cell density (P=0.39), and CD4+ FOXP3+ T-cell density (P=0.68) did not significantly differ, but the percentage of CD4+ Tbet+ T-cells (Th1 phenotype) was also significantly higher in responders than nonresponders (P=0.0007).
Conclusions: Higher densities of CD8+ TILs, PD-1-expressing CD8+ TILs, and tumor-infiltrating immune cells with a Th1 phenotype in the TME may predict response to checkpoint inhibitors in MSI-H and POLE-mutated mCRC.
Methods: Immune profiling through multispectral fluorescent immunohistochemistry (IHC) using a multimarker staining panel was performed on pretreatment tumor specimens from a cohort of MSI-H or POLE mCRC patients treated with PD-1 blockade at our institution to identify candidate predictors of response to checkpoint inhibitors.
Results: From 4/2013 to 1/2017, a total of 237 mCRC patients with molecularly profiled tumors were screened. Five MSI-H and three POLE-mutated mCRC patients were treated with checkpoint inhibitors. Immune profiling identified higher CD8+ tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment (TME) of responders (CR or PR as best response) than nonresponders (SD or PD as best response). Responders had significantly higher densities of CD8+ PD-1+ TILs than nonresponders (P=0.0007). PD-L1 expression (P=0.73), CD4+ T-cell density (P=0.39), and CD4+ FOXP3+ T-cell density (P=0.68) did not significantly differ, but the percentage of CD4+ Tbet+ T-cells (Th1 phenotype) was also significantly higher in responders than nonresponders (P=0.0007).
Conclusions: Higher densities of CD8+ TILs, PD-1-expressing CD8+ TILs, and tumor-infiltrating immune cells with a Th1 phenotype in the TME may predict response to checkpoint inhibitors in MSI-H and POLE-mutated mCRC.
