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. 2024 Jan 9:13:1225820.
doi: 10.3389/fonc.2023.1225820. eCollection 2023.

Molecular epidemiology study of programmed death ligand 1 and ligand 2 protein expression assessed by immunohistochemistry in extensive-stage small-cell lung cancer

Torben Steiniche  1 , Jeanette Baehr Georgsen  1 , Peter Meldgaard  2 , Anne C Deitz  3 , Mark Ayers  3 , M Catherine Pietanza  3 , Ke Zu  3
Affiliations

Molecular epidemiology study of programmed death ligand 1 and ligand 2 protein expression assessed by immunohistochemistry in extensive-stage small-cell lung cancer

Torben Steiniche et al. Front Oncol. .

Abstract

Objectives: Prevalence of tumor PD-L1 expression in extensive-stage small-cell lung cancer (ES-SCLC) is variable, and data on PD-L2 expression are limited. The prognostic values of these biomarkers are not well understood. The current study was conducted to address these data gaps.

Methods: A retrospective cohort study of Danish patients with histologically confirmed ES-SCLC and evaluable tumor samples who were receiving usual care before the introduction of immunotherapy was conducted. Protein expression of PD-L1 and PD-L2 was determined by immunohistochemistry (IHC) using the PD-L1 IHC 22C3 pharmDx assay and a PD-L2 IHC assay using a propriety mouse monoclonal antibody. A combined positive score (CPS) of ≥1 was used to define biomarker positivity. Kaplan-Meier plots and Cox proportional hazard models were employed to assess the relationship between PD-L1 and PD-L2 protein expression and OS.

Results: Among 80 patients, 31% (n=25) and 36% (n=29) had disease positive for PD-L1 and PD-L2, respectively. Overall, 85% (n=68) of patients had concordant PD-L1/PD-L2 status; 26% (n=21) had double positive disease (both PD-L1 and PD-L2 CPS ≥1) and 59% (n=47) had double negative disease (both PD-L1 and PD-L2 CPS <1). PD-L1 and PD-L2 positivity were each associated with longer OS (unadjusted hazard ratios [HRs], 0.35 [95% CI, 0.21-0.61] and 0.50 [95% CI, 0.31-0.82]); the associations persisted after adjustment for several known prognostic factors (HRs, 0.41 [95% CI, 0.22-0.75] and 0.44 [95% CI, 0.25-0.79] for PD-L1 and PD-L2 positivity, respectively). When evaluating OS in patients with double positive disease, unadjusted and adjusted HRs for double positive compared with double negative were similar to those with only PD-L1 or PD-L2 positivity (unadjusted HR, 0.36 [95% CI, 0.20-0.64]; adjusted HR, 0.36 [0.18-0.73]).

Conclusion: PD-L1 and PD-L2 positivity were observed in approximately one-third of assessed ES-SCLC tumor samples and were highly congruent. Patients with PD-L1 and PD-L2 positivity, alone or combined, were associated with longer OS, independent of other prognostic factors.

Keywords: PD-L1; PD-L2; biomarker; extensive-stage small-cell lung cancer; prevalence.

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Conflict of interest statement

TS: Employee of Aarhus University Hospital, who received funding from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, to conduct this study. Fiduciary role for the Danish Medicines Council as a member of a subgroup concerning targeted treatment of cancer regardless of the histological type. JBG: Employee of Aarhus University Hospital, Region Midt, Denmark, who received funding from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, to conduct this study PM: Employee of Aarhus University Hospital, who received funding from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, to conduct this study. KZ, ACD, MA, and MCP: Employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and stockholders of Merck & Co., Inc., Rahway, NJ, USA.

Figures

Figure 1
Figure 1
Representative fields (x20) of IHC staining for PD-L1 and PD-L2 in SCLC tumor tissue samples. (A) PD-L1 negative (CPS = 0), (B) PD-L2 negative (CPS = 0), (C) PD-L1 positive (CPS = 40), and (D) PD-L2 positive (CPS = 40). Arrows indicate representative areas of positive staining for PD-L1 (C) and PD-L2 (D).
See this image and copyright information in PMC

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