Intra-tumoral heterogeneity in the expression of programmed-death (PD) ligands in isogeneic primary and metastatic lung cancer: Implications for immunotherapy

Purpose: There is inconclusive evidence to suggest the expression of programmed cell death (PD) ligand 1 (PD-L1) is a putative predictor of response to PD-1/PD-L1-targeted therapies in lung cancer. We evaluated the heterogeneity in the expression of PD-1 ligands in isogeneic primary and metastatic LC specimens. Experimental Design: From 12,580 post mortem cases, we identified 214 patients with untreated metastatic LC, of which 98 had adequately preserved tissues to construct a syngeneic primary LC/metastasis tissue microarray. Immunostaining for PD-L1 and 2 was evaluated in paired primary and metastatic lesions and correlated with clinicopathologic features. Results: We included 98 patients with non-small cell (NSCLC, n = 65, 66%), small cell histology (SCLC, n = 29, 30%) and four (4%) atypical carcinoids (AC). In total 8/65 (12%) primary PD-L1 positive NSCLC, had discordant matched metastases (14/17, 82%). PD-L1 negative primaries had universally concordant distant metastases. SCLCs were universally PD-L1 negative across primary and metastatic disease. PD-L2 positive NSCLC (n = 11/65, 17%) had high rate of discordant metastases (n = 24/27, 88%) and four cases (6%) had PD-L2 positive metastases with negative primaries. 2/29 SCLC (7%) and 1/4 AC (25%) were PD-L2 positive with discordance in all the sampled metastatic sites (n = 5). We found no correlation between the expression of PD ligands and clinicopathologic features of LC. Conclusions: Intra-tumoral heterogeneity in the expression of PD ligands is common in NSCLC, while PD-L1 is homogeneously undetectable in primary and metastatic SCLC. This holds implications in the clinical development of immune response biomarkers in LC.