Cancer immunotherapy

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PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to Pembrolizumab

Recently, it was reported a 56% objective response rate in patients with advanced Merkel cell carcinoma ( MCC ) receiving Pembrolizumab ( Keytruda ).
However, a biomarker predicting clinical response was not identified.

Pretreatment FFPE ( formalin-fixed, paraffin-embedded ) tumor specimens ( n = 26 ) were stained for CD8, PD-L1, and PD-1 by immunohistochemistry / immunofluorescence ( IHC/IF ), and the density and distribution of positive cells was quantified to determine the associations with anti-PD-1 response.
Multiplex immunofluorescence was used to test a separate cohort of Merkel cell carcinoma archival specimens ( n = 16 ), to identify cell types expressing PD-1.

Tumors from patients who responded to anti-PD-1 showed higher densities of PD-1+ and PD-L1+ cells when compared to non-responders ( median cells/mm2, 70.7 vs. 6.7, p = 0.03; and 855.4 vs. 245.0, p = 0.02, respectively ).

There was no significant association of CD8+ cell density with clinical response.

Quantification of PD-1+ cells located within 20 microm of a PD-L1+ cell showed that PD-1/PD-L1 proximity was associated with clinical response ( p = 0.03 ), but CD8/PD-L1 proximity was not.
CD4+ and CD8+ cells in the tumor microenvironment expressed similar amounts of PD-1.

In conclusion, the binomial presence or absence of PD-L1 expression in the tumor microenvironment was not sufficient to predict response to anti-PD-1 in patients with Merkel cell carcinoma.
Quantitative assessments of PD-1+ and PD-L1+ cell densities as well as the geographic interactions between these two cell populations showed correlate with clinical response.
Cell types expressing PD-1 in the tumor microenvironment include CD8+ T-cells, CD4+ T-cells, Tregs, and CD20+ B-cells, supporting the notion that multiple cell types may potentiate tumor regression following PD-1 blockade. ( Xagena )

Giraldo NA et al, J Immunother Cancer 2018; 6(1):99. doi: 10.1186/s40425-018-0404-0.