PD-L1 Expression in Metastatic
Cutaneous Squamous Cell Carcinomas
Nathaniel A. Slater, MD1, James Tidwell, MD2, George Sonnier, MD2, Paul Googe, MD1,3
1Department
of Dermatology, University of North Carolina School of Medicine, Chapel Hill, NC, USA 2University of Louisville Division of Dermatology,
Louisville, KY, USA 3Knoxville Dermatopathology Laboratory, Knoxville, TN, USA
Introduction: PD-1 / PD-L1 Axis
To date, several case reports have demonstrated response to therapy targeting the PD1 / PDL1 axis of regionally advanced or metastatic cutaneous squamous cell carcinoma not
amenable to surgical treatment modalities [cite]. In some cases, PD-1 / PD-L1 checkpoint
blockade has also resulted in durable remissions in other cancer types including NSMLC.
Currently, 2 PD-1 directed antibodies are approved for treatment of certain advanced
malignancies; others are in development. Immunotherapies targeting the PD-1/PD-L1 axis
appear to have less toxicity than CTLA-4 blockade.
PD-L1 is a transmembrane protein involved in regulation of cellular and humoral immune
responses. PD-L1 is mainly expressed on antigen presenting cells, activated T and B cells,
placenta. PD-1 (receptor) is broadly expressed on activated lymphoid cells. It is also highly
expressed on regulatory T cells, and over-expressed on exhausted T cells. Interaction of PDL1 with receptor PD-1 helps regulate T cell activation and tolerance during pregnancy, tissue
allografts, and in autoimmune disease.
PD-1 predominantly regulates
effector functions of activated T cells.
PD-1/PD-L1 interaction inhibits
proliferation and cytotoxic program of
CD8+ T cells, and promotes
regulatory T cell differentiation. PD-1
expression on CD8+ T cells has been
associated with functional impairment
of tumor infiltrating lymphocytes in
HCC, melanoma, Hodgkin’s, and
RCC.
Assessing PD-L1 Expression in cSCC
Collated findings from 15 metastatic SCC cases, in comparison with 40 primary
cutaneous SCC cases as previously published
Negative PD-L1 expression
H&E, low power
PD-L1, low power
No Expression: Partial or
complete cell membrane staining
(≥ 1+) in < 1% of viable tumor
cells
H&E, high power
PD-L1 Expression in Metastatic cSCC
PD-L1, high power
Left: 1.9cm grade 2 SCC
invasive to subcutaneous fat,
7.7mm depth. No PD-L1
expression observed in
constitutive skin structures. There
is only focal reactivity for PD-L1
in tumor-infiltrating lymphocytes
(TILs, arrow); TILs expressed at
least focal PD-L1 in nearly all
cases
PD-L1 Expression in Viable Tumor Cells of 40 Primary Cutaneous SCCs and
15 Loco-regional Metastatic Cutaneous SCCs
Low Risk SCCs
High Risk SCCs Metastatic SCCs
PDL Expression
(n = 20)
(n = 20)
(n = 15)
PD-L1 Tumor
N (%)
Proportion Score
Negative
Low
High
Mean % of tumor
cells PD-L1
positive (range)
16 (80)
6 (30)
4 (27)
4 (20)
0 (0)
12 (60)
2 (10)
9 (60)
2 (13)
2% (0 – 25)
20% (0 – 90)
24% (4 – 90)
Difference in
Tumor Proportion
Score categories,
Low Risk vs
Metastatic SCCs:
p = 0.004 (Fisher’s
exact test)
Metastatic case with low expression of PD-L1 (low and high power)
Low PD-L1 expression
H&E, low power
Gianchecchi et al.
Malignancies can hijack this pathway to evade host anti-tumor
response. PD-L1 expression has been found on some tumors such as melanoma,
DLBCL, Hodgkin’s, triple negative breast ca, and carcinomas of the GI, GU, and
pulmonary tracts. PD-L1 in pulmonary adenocarcinoma has been shown to correlate with
histologic subtypes portending poorer prognosis. Overall however, the association
between PD-L1 expression and prognosis is unclear.
Mostly extrinsic induction of
PD-L1 as acquired adaptive
immune evasion. IFNγ can
upregulate PD-L1 on tumor
cells as well as TILs. MAPK
over-activation, loss of PTEN
implicated among other
pathways. 5-10% of tumors
express PD-L1 constitutively
PD-L1, low power
Low Expression: Partial or
complete cell membrane
staining (≥ 1+) in 1–49% of
viable tumor cells
H&E, high power
PD-L1, high power
High PD-L1 expression
PD-L1, low power
High Expression: Partial
or complete cell membrane
staining (≥ 1+) in ≥ 50% of
viable tumor cells
Pardoll et al.
Methods
We have previously described expression of programmed cell death ligand 1 (PD-L1) in 40
primary and 5 regionally advanced or metastatic cutaneous squamous cell carcinomas, and
documented correlation of PD-L1 with histologic features which increase risk for metastasis
[cite]. We here report a follow up to our previous study with the investigation of ten additional
metastatic cases of cutaneous squamous cell carcinoma. Cases were collated from the files
of [ ]. Immunohistochemical staining with anti PD-L1 antibody was performed at the Knoxville
Dermatopathology Laboratory as previously described. Cases were reviewed by all four
authors, and PD-L1 expression was categorized by the DAKO tumor proportion score
method as negative, low, or high, as illustrated in the following panel.
Left: 2.4cm grade 2 SCC
invasive to subcutaneous fat,
7.2mm depth. Low PD-L1
expression visible in
approximately 40% of
carcinoma cells, mostly
present at periphery of tumor.
At higher power, PD-L1
reactivity is complete along the
tumor cell membranes and of
moderate intensity
H&E, low power
H&E, high power
PD-L1, high power
Metastatic cutaneous SCC with high expression of PD-L1 (H&E and immunostain)
Left: 2.3cm grade 4 SCC
invasive to subcutaneous
fat, 9mm depth. High PD-L1
expression is visible in
approximately 90% of
viable tumor cells.
Brisk TILs are evident at the
border of the tumor.
Complete strong staining
for PD-L1 is seen on tumor
cell membranes.
Conclusions
• This study documents PD-L1 expression in an expanded series of metastatic cutaneous
squamous cell carcinoma.
• PD-L1 is expressed to a higher degree in locally advanced and regionally metastatic
cases compared with low risk cutaneous SCCs
• Histologically, expression seen often in areas of robust immune response
• Remarkably high levels of PD-L1 expression were observed in several locally advanced
and metastatic cases
• Limitations include lack of clinical correlation
• Relevance of PD-L1 in advanced cSCC is still unclear
Acknowledgements
Thank you to Paul Googe, MD, for mentorship on this project, and to Susan Foreman and
Ada Brannan-Ramsey of Knoxville Dermatopathology lab for expert immunostaining
References
• Slater NA, Googe PB. PD-L1 expression in cutaneous squamous cell carcinoma correlates with
risk of metastasis. J Cutan Pathol. May 2016 (see for complete list of references)
• Gianchecchi E, Delfino DV, Fierabracci A. Recent insights into the role of the PD-1/PD-L1 pathway
in immunological tolerance and autoimmunity. Autoimmun Rev. 2013;12(11):1091-1100.
• Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer.
2012;12(4):252-264.