This article is more than 5 years old. Information may no longer be current.
Researchers aim to define relevance of PD-L1 in diffuse large B-cell lymphoma
Click Here to Manage Email Alerts
PD-L1 positivity did not identify high-risk patients with de novo diffuse large B-cell lymphoma and may be associated with improved prognosis in a subset of patients, according to an analysis of the GOYA and MAIN trials published in Blood Advances.
Further, PD-L1 expression primarily occurred on myeloid cells and correlated with macrophage and STAT3 expression.
“Among de novo DLBCL patients, high PD-L1 expression and soluble PD-L1 have been correlated with both inferior and superior clinical outcomes, possibly attributable to different patient populations, different PD-L1 reagents, or a more complex PD-L1 biology within this heterogeneous disease,” Jeffrey M. Venstrom, MD, franchise lead at Genentech, and colleagues wrote. “In de novo DLBCL patients treated with immunochemotherapy, specific PD-L1 expression by malignant B cells is associated with worse outcome. However, accurate estimation of tumor-specific PD-L1 staining is challenging, with most studies suggesting that tumor-specific PD-L1 expression is rare, possibly limited to a small percentage of the activated B-cell (ABC) subtype of DLBCL, and may depend on the PD-L1 reagent.”
To better understand the biologic and clinical relevance of PD-L1 in de novo DLBCL, Venstrom and colleagues evaluated data from 552 patients (median age, 63 years; 52.2% men) from the GOYA trial and 225 patients (median age, 62 years; 47.6% men) from the MAIN trial.
Overall, 433 patients with DLBCL had available PD-L1 immunohistochemistry results. Based on the PD-L1 immunohistochemistry reagent used — SP142 or SP263 — 85% to 95% of patients expressed PD-L1 on myeloid cells. However, only 10% of patients from the MAIN trial and 5.6% of patients from the GOYA trial expressed PD-L1 on tumor cells.
RNA analysis of 702 patients showed CD274 mRNA correlated with PD-L1 staining by immunohistochemistry. CD274 mRNA was higher among patients with the ABC subtype in the MAIN (P = .01) and GOYA (P = .004) trials.
Results also showed that macrophage gene expression correlated with PD-L1 protein expression by SP263 (MAIN, r = 0.36; GOYA, r = 0.35) and with CD274 mRNA expression (MAIN, r = 0.61; GOYA, r = 0.57).
Researchers then explored mechanistic signaling pathways tied to PD-L1 by analyzing the association of CD274 mRNA with pathways implicated in controlling PD-L1 expression. They found that STAT3 (r = 0.48) and a STAT3 gene signature (r = 0.63) correlated with CD274 gene expression.
High PD-L1 protein expression on the SP263 reagent correlated with prolonged PFS (HR = 0.44; 95% CI, 0.24-0.8) and OS (HR = 0.33; 95% CI, 0.17-0.65) in the MAIN trial; however, these outcomes did not appear significant when using the SP142 reagent or when assessing CD274 mRNA expression.
Among 552 patients treated in GOYA, the 91% with high PD-L1 by SP263 did not show significantly prolonged PFS (HR = 0.63; 95% CI, 0.37-1.1) or OS (HR = 1.4; 95% CI, 0.74-2.5).
High expression of the macrophage signature correlated with prolonged PFS (HR = 0.63; 95% CI, 0.45-0.87) and OS (HR = 0.54; 95% CI, 0.37-0.78) in GOYA, particularly among those with the ABC subtype (PFS, HR = 0.38; 95% CI, 0.18-0.8). Researchers observed a similar trend in the MAIN trial, but it did not reach statistical significance.
Further, high STAT3 mRNA similarly correlated with prolonged PFS (HR = 0.67; 95% CI, 0.48-0.93) in GOYA, “suggesting that high STAT3 signaling among tumor-associated macrophages may contribute to PD-L1 expression in DLBCL,” the researchers wrote.
“In our DLBCL cohorts, high STAT3 expression correlated with PD-L1 and macrophage gene expression and prolonged PFS among patients treated in GOYA, suggesting a functional relationship between STAT3 signaling, macrophages and PD-L1 expression in de novo DLBCL,” the researchers wrote.
“Future studies should explicitly examine the effect of PD-L1-expressing myeloid cell subsets on clinical outcomes and phagocytic potential, with implications for anti-CD20, anti-PD-1/PD-L1, and other myeloid targeting therapies like anti-CSF1R,” they added. – by Alexandra Todak
Disclosures: Venstrom and other authors report employment with and stock ownership in Genentech and Roche.
Click Here to Manage Email Alerts