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BRAF and MEK Inhibitors Increase PD-1-Positive Melanoma Cells Leading to a Potential Lymphocyte-Independent Synergism with Anti-PD-1 Antibody
Ist Teil von
Clinical cancer research, 2018-07, Vol.24 (14), p.3377-3385
Ort / Verlag
United States: American Association for Cancer Research Inc
Erscheinungsjahr
2018
Quelle
Free E-Journal (出版社公開部分のみ)
Beschreibungen/Notizen
BRAF and MEK inhibitors (BRAF/MEKi) favor melanoma-infiltrating lymphocytes, providing the rationale for current combinatorial trials with anti-PD-1 antibody. A portion of melanoma cells may express PD-1, and anti-PD-1 antibody could have a direct antitumor effect. Here, we explore whether BRAF/MEKi modulate rates of PD-1
melanoma cells, supporting an additional-lymphocyte-independent-basis for their therapeutic combination with anti-PD-1 antibody.
With data mining and flow cytometry, we assessed PD-1, PD-L1/2 expression on melanoma cell lines (CCLE,
= 61; validation cell lines,
= 7) and melanoma tumors (TCGA,
= 214). We explored
how BRAF/MEKi affect rates of PD-1
, PD-L1/2
melanoma cells, and characterized the proliferative and putative stemness features of PD-1
melanoma cells. We tested the functional lymphocyte-independent effect of anti-PD-1 antibody alone and in combination with BRAF/MEKi
and in an
immunodeficient murine model.
PD-1 is consistently expressed on a small subset of melanoma cells, but PD-1
cells increase to relevant rates during BRAF/MEKi treatment [7.3% (5.6-14.2) vs. 1.5% (0.7-3.2),
= 0.0156;
= 7], together with PD-L2
melanoma cells [8.5% (0.0-63.0) vs. 1.5% (0.2-43.3),
= 0.0312;
= 7]. PD-1
cells proliferate less than PD-1
cells (avg. 65% less;
= 7 days) and are preferentially endowed with stemness features.
, the direct anti-melanoma activity of PD-1 blockage as monotherapy was negligible, but its association with BRAF/MEKi significantly delayed the development of drug resistance and tumor relapse.
BRAF/MEKi increase the rates of PD-1
melanoma cells that may sustain tumor relapse, providing a lymphocyte-independent rationale to explore combinatory strategies with anti-PD-1 antibody.
.