title: Immune-Derived PD-L1 Gene Expression Defines a Subgroup of Stage II/III Colorectal Cancer Patients with Favorable Prognosis Who May Be Harmed by Adjuvant Chemotherapy.
abstract: A recent phase II study of patients with metastatic colorectal carcinoma 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 colorectal carcinoma, suggesting that the amount of PD-L1 protein expression could identify late-stage patients who might benefit from immunotherapy. To assess whether the clinical associations between PD-L1 gene expression and MSI identified in metastatic colorectal carcinoma are also present in stage II/III colorectal carcinoma, we used in silico analysis to elucidate the cell types expressing the PD-L1 gene. We found a statistically significant association of PD-L1 gene expression with MSI in early-stage colorectal carcinoma (P < 0.001) and show that, unlike in non-colorectal carcinoma 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) vs. 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). Building on the promising results from the metastatic colorectal carcinoma PD-1-targeting trial, we provide compelling evidence that patients with PD-L1(high)/MSI/immune(high) stage II/III colorectal carcinoma should not receive standard chemotherapy. This conclusion supports the rationale to clinically evaluate this patient subgroup for PD-1 blockade treatment. Cancer Immunol Res; 4(7); 582-91. ©2016 AACR.
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Dunne
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Darragh G
authors.initials: DG
authors.lastname: McArt
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Paul G
authors.initials: PG
authors.lastname: O'Reilly
authors.affiliation: Centre for Public Health, Queen's University Belfast, Belfast, UK.
authors.forename: Helen G
authors.initials: HG
authors.lastname: Coleman
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Allen
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK. Department of Histopathology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, UK.
authors.forename: Maurice
authors.initials: M
authors.lastname: Loughrey
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: Van Schaeybroeck
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: McDade
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Longley
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK. mark.lawler@qub.ac.uk.
authors.forename: Mark
authors.initials: M
authors.lastname: Lawler
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Johnston
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000235:genetics*; D017024:Chemotherapy, Adjuvant; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D030561:Databases, Nucleic Acid; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D060890:B7-H1 Antigen