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Keith M. Kerr, BSc, MB, ChB, FRCPath, FRCPE; Marianne C. Nicolson, MD, FRCP
sponse to minimize collateral tissue damage. These mechanisms are also important in creating immune tolerance and
the prevention of autoimmune disease. Their importance in
inhibiting an effective immune response to tumor antigen
makes them attractive targets for therapeutic intervention.
In terms of malignant disease, one of the first inhibitory
immune checkpoints to be targeted was cytotoxic Tlymphocyteassociated protein 4 (CTLA-4), an immune
checkpoint receptor that is exclusively expressed on T cells,
with CD80 and CD86 as ligands.10 Recently, however, much
attention has been paid to PD-1 and its ligand PD-L1 and
how this interaction might be blocked in NSCLC by
immunomodulatory therapies, such as therapeutic monoclonal antibodies specific for either PD-1 or PD-L1.
PD-1 AND PD-L1 BIOLOGY
PD-1 is expressed by T cells, including Tregs, but also by
NK cells and some B cells. It is involved in the later stages of
the immune response, regulating the activation of T cells in
peripheral tissues. PD-1 has two ligands, PD-L1 (also
known as B7-H1 or CD274) and PD-L2 (B7-DC or CD273).
These ligands are expressed on a wide range of immune
effector cells, antigen-presenting cells, and TCs. The
expression of PD-L1 by TCs may be a key mechanism by
which they inhibit immune activity. This expression may be
constitutive, related to abnormal TC gene expression. In
some tumors loss of phosphatase and tensin homolog
(PTEN) expression and upregulation of the protein kinase
Bphosphatidylinositol-3-kinase (AKT-PI3K) pathways has
been implicated, whereas signal transducer and activator of
transcription 3 (STAT3) signaling may be involved in
anaplastic lymphoma kinase (ALK) rearranged lung cancers.10 PD-L1 gene amplification is also seen in some tumors
and is associated with high levels of PD-L1 protein in TCs.14
PD-L1 expression may also be induced by interferon c,
which is produced largely by T-helper 1 cells as part of a
host inflammatory response; this process is referred to as
adaptive immune resistance. PD-L1 expression is heterogeneous within tumors and may be seen more frequently in
areas of tumor with higher levels of tumor-infiltrating
lymphocytes.10 However, this is at odds with an observation
recently reported where, using the SP142 clone for PD-L1
immunohistochemistry (IHC), cancers expressing high
levels of PD-L1 in TCs lacked high numbers of tumorinfiltrating lymphocytes, and those tumor-infiltrating lymphocytes present lacked much PD-L1 expression.14 The
same study also reported that tumors with high levels of
PD-L1positive tumor-infiltrating lymphocytes tended to be
rich in CD8 cells, whereas those with high PD-L1
expression in TCs tended to have a sclerotic stroma and
few CD8 cells. The exact implications of these observed
interrelationships are not clear, and much more work is
required to clarify understanding of such complex biology.
The fact that PD-L1 is inducible by inflammatory cytokines
released into the TC microenvironment is important when
considering the findings of PD-L1 expression studies in
samples from patients with NSCLC (see below). Studies of
PD-L1 expression in lung cancer report a prevalence of 13%
to 70% positivity for this biomarker, partly dependent on
how expression is tested for and defined.15 There is also
evidence that higher expression of PD-L1 in surgically
resected NSCLC is a poor prognostic factor, implicating
down-regulation of the host immune response to the tumor
as a means of ensuring TC survival.16,17 Conversely, evidence
PD-L1 Testing in NSCLCKerr & Nicolson
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