PD-L1 and Emerging Biomarkers in Immune Checkpoint Blockade Therapy

Abstract

PD-L1 checkpoint blockade is revolutionizing cancer therapy, and biomarkers capable of predicting which patients are most likely to respond are highly desired. The detection of PD-L1 protein expression by immunohistochemistry can enrich for response to anti-PD-(L)1 blockade in a variety of tumor types, but is not absolute. Limitations of current commercial PD-L1 immunohistochemical (IHC) assays and improvements anticipated in next-generation PD-L1 testing are reviewed. Assessment of tumor-infiltrating lymphocytes in conjunction with PD-L1 testing could improve specificity by distinguishing adaptive (interferon γ driven and cytotoxic T-lymphocyte associated) from constitutive (non-immune mediated) expression. The presence of a high tumor mutational burden also enriches for response to therapy, and early data indicate that this may provide additive predictive value beyond PD-L1 IHC alone. As candidate biomarkers continue to emerge, the pathologist's assessment of the tumor microenvironment on hematoxylin-eosin stain combined with PD-L1 IHC remains a rapid and robust way to evaluate the tumor-immune dynamic.

Figure 1. Photomicrograph showing the geographic assessment of lymphocyte infiltrates in the tumor microenvironment

(A) A dense population of small lymphocytes (white arrows) is present in the peritumoral stroma along the leading edge of the tumor (white line). Although fewer in number, tumor infiltrating lymphocytes (white arrowheads) are also intermixed among larger tumor cells (asterisks) more centrally within the tumor. (B) A non-inflamed tumor composed almost exclusively of large tumor cells without admixed lymphocytes. (C) An inflamed tumor with numerous small lymphocytes (white arrows) among the larger tumor cells (yellow arrows). Hematoxylin and eosin (H&E) stain, Original magnification 200x.

Figure 2. Hive plot for demonstrating the relationship between PD-L1 expression, CYT (cytotoxic gene signature expression), and mutational load in multiple common solid tumor types

Comparisons of PD-L1 and CYT expression levels amongst different tumor types have been challenging due to the diverse assays used across studies. TCGA public datasets were used to determine the relative expression levels of PD-L1 and CYT (combined GZMA_PRF1 transcript levels, indicating cytolytic effector activity). for nine solid tumor types (SKCM, melanoma; KIRC, renal cell carcinoma; LUSC, squamous cell carcinoma of the lung; LUAD, lung adenocarcinoma; COAD, colonic adenocarcinoma; HNSC, head and neck squamous cell carcinoma; PAAD, pancreatic adenocarcinoma; BRCA, breast carcinoma; BLCA, bladder carcinoma). Each axis increases in value as it extends from the center of the plot. The highest levels of median PD-L1 expression are seen in the tumor types with squamous differentiation, consistent with the known constitutive expression in these tumor types. Notably, PD-L1 expression levels and CYT track each other closely, while mutational density tends to be less aligned.