PD-1 and PD-L1 Expression in Renal Cell Carcinoma with Sarcomatoid Differentiation

Abstract

Monoclonal antibodies that target the programmed death-1 (PD-1)-programmed death ligand-1 (PD-L1) axis have antitumor activity against multiple cancers. The presence of sarcomatoid differentiation in renal cell carcinoma (RCC) is associated with resistance to targeted therapy and poor responses to IL2 immunotherapy. Given the aggressive nature of RCC with sarcomatoid differentiation and the exclusion of sarcomatoid histology from metastatic RCC clinical trials, less is understood regarding selection of therapies. Here, we characterized the PD-1/PD-L1 axis in RCC with sarcomatoid differentiation. We directly compared two PD-L1 antibodies and found concordance of PD-L1 positivity in 89% of tested RCCs with sarcomatoid differentiation. Coexpression of PD-L1 on neoplastic cells and the presence of PD-1-positive tumor-infiltrating lymphocytes were identified in 50% (13 of 26) of RCCs with sarcomatoid differentiation. In contrast, only 1 of 29 clear cell RCCs (3%) had concurrent expression of PD-L1 and PD-1 (P = 0.002). Our study suggests that RCC with sarcomatoid differentiation may express PD-1/PD-L1 at a higher percentage than RCC without sarcomatoid differentiation, and patients with these tumors may be good candidates for treatment with anti-PD-1/PD-L1 therapies.

Figure 1

Representative PD-L1 Immunohistochemical Staining in Two Samples of RCC With Sarcomatoid Differentiation. A and B, Hematoxylin-eosin staining (H+E). C and D, Staining with SP142 anti–PD-L1 antibody showing positive (C) and negative staining (D). E and F, Staining with 130021 anti–PD-L1 antibody showing positive (E) and negative staining (F). Panels A, C, and E are from a PD-L1 positive RCC. Panels B, D, and F are from a PD-L1 negative RCC. All panels, original magnification ×20.

Figure 2

Representative Immunohistochemical Staining of PD-1 Expression in RCC With Sarcomatoid Features and Clear Cell RCC. Staining of sarcomatoid (A and C) and ccRCC (B and D) samples. A and B, Hematoxylin-eosin staining (H+E). C and D, Staining with anti–PD-1 antibody showing positive staining of sarcomatoid RCC (C) and negative staining of ccRCC (D). All panels, original magnification ×20. E, Percentage of tumors with PD-L1 expression (clone 130021), PD-1⁺ tumor-infiltrating lymphocytes, or coexpression of PD-L1 and PD-1 in sarcomatoid RCC or ccRCC.

Figure 3

PD-L1 Expression and Tumor Response to Anti–PD-1 Immunotherapy in a Patient With Metastatic RCC With Sarcomatoid Differentiation. A–C, Staining of biopsied tumor nodule with hematoxylin-eosin (A), with antibody SP142 to PD-L1 (B) or with antibody 130021 to PD-L1 (C). All panels, original magnification ×40. D and E, Serial computed tomographic imaging of biopsied tumor nodule (arrow) before (D) and after (E) initiation of pembrolizumab.