Immune-derived PD-L1 gene expression defines a subgroup of stage II/III colorectal cancer patients with favorable prognosis that may be harmed by adjuvant chemotherapy


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Philip Dunne1,Darragh McArt2,Paul O'Reilly2,Helen Coleman2,Maurice Loughrey2,Wendy Allen2,Simon McDade2,Sandra van Scaheybroeck2,Manuel Salto-Tellez2,Daniel Longley2,Mark Lawler2,Patrick Johnston2
1CCRCB Queen's University Belfast,2QUB

Abstract

Background

A recent phase 2 study of metastatic colorectal carcinoma (CRC) patients showed that mismatch repair gene status was predictive of clinical response to PD-1-targeting immune checkpoint blockade. Further examination revealed strong correlation between PD-L1 protein expression and microsatellite instability (MSI) in stage IV CRC, suggesting that the amount of PD-L1 protein expression could identify late stage patients who may benefit from immunotherapy.

Method

To assess whether the clinical associations between PD-L1 gene expression and MSI identified in metastatic CRC are also present in stage II/III CRC, we used in silico analysis methods in a number of clinical datasets to elucidate both the clinical importance of PD-L1 gene expression in stage II/III CRC and the precise cell types expressing the PD-L1 gene.

Results

We found a significant association of PD-L1 gene expression with MSI in early stage CRC (P < 0.001) and show that unlike in non-CRC tumors, PD-L1 is derived predominantly from the immune infiltrate. We demonstrate that PD-L1 gene expression has positive prognostic value in the adjuvant disease setting (PD-L1-low v PD-L1-high HR = 9.09; CI, 2.11-39.10). PD-L1 gene expression had predictive value, as patients with high PD-L1 expression appear to be harmed by standard-of-care treatment (HR = 4.95; CI,1.10-22.35).

Conclusion

Building on the promising results from the metastatic CRC PD-1-targeting trial, we provide compelling evidence that PD-L1-high/MSI/immune-high stage II/III CRC patients should not receive standard chemotherapy. This conclusion supports the rationale to clinically evaluate this patient subgroup for PD-1 blockade treatment.