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. .
The immune response to the K99 was tested in 45 pregnant cows, subcutaneously vaccinated, for protecting the newborn calves. Serological tests were performed in the blood sera of all animals and in the milk and colostrum sera; hemogram, inhibition of the adhesion to the brush border and histological tests were performed. The calves from vaccinated cows survived the experimental infection after the suction of colostrum in spite of the fact that the calves from control dams died with diarrhea.
<div>Abstract<p><b>Purpose:</b> 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<sup>+</sup> melanoma cells, supporting an additional—lymphocyte-independent—basis for their therapeutic combination with anti–PD-1 antibody.</p><p><b>Experimental Design:</b> With data mining and flow cytometry, we assessed PD-1, PD-L1/2 expression on melanoma cell lines (CCLE, <i>N</i> = 61; validation cell lines, <i>N</i> = 7) and melanoma tumors (TCGA, <i>N</i> = 214). We explored <i>in vitro</i> how BRAF/MEKi affect rates of PD-1<sup>+</sup>, PD-L1/2<sup>+</sup> melanoma cells, and characterized the proliferative and putative stemness features of PD-1<sup>+</sup> melanoma cells. We tested the functional lymphocyte-independent effect of anti–PD-1 antibody alone and in combination with BRAF/MEKi <i>in vitro</i> and in an <i>in vivo</i> immunodeficient murine model.</p><p><b>Results:</b> PD-1 is consistently expressed on a small subset of melanoma cells, but PD-1<sup>+</sup> cells increase to relevant rates during BRAF/MEKi treatment [7.3% (5.6–14.2) vs. 1.5% (0.7–3.2), <i>P</i> = 0.0156; <i>N</i> = 7], together with PD-L2<sup>+</sup> melanoma cells [8.5% (0.0–63.0) vs. 1.5% (0.2–43.3), <i>P</i> = 0.0312; <i>N</i> = 7]. PD-1<sup>+</sup> cells proliferate less than PD-1<sup>−</sup> cells (avg. 65% less; <i>t</i> = 7 days) and are preferentially endowed with stemness features. <i>In vivo</i>, 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.</p><p><b>Conclusions:</b> BRAF/MEKi increase the rates of PD-1<sup>+</sup> melanoma cells that may sustain tumor relapse, providing a lymphocyte-independent rationale to explore combinatory strategies with anti–PD-1 antibody. <i>Clin Cancer Res; 24(14); 3377–85. ©2018 AACR</i>.</p></div>
<div>Abstract<p><b>Purpose:</b> 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<sup>+</sup> melanoma cells, supporting an additional—lymphocyte-independent—basis for their therapeutic combination with anti–PD-1 antibody.</p><p><b>Experimental Design:</b> With data mining and flow cytometry, we assessed PD-1, PD-L1/2 expression on melanoma cell lines (CCLE, <i>N</i> = 61; validation cell lines, <i>N</i> = 7) and melanoma tumors (TCGA, <i>N</i> = 214). We explored <i>in vitro</i> how BRAF/MEKi affect rates of PD-1<sup>+</sup>, PD-L1/2<sup>+</sup> melanoma cells, and characterized the proliferative and putative stemness features of PD-1<sup>+</sup> melanoma cells. We tested the functional lymphocyte-independent effect of anti–PD-1 antibody alone and in combination with BRAF/MEKi <i>in vitro</i> and in an <i>in vivo</i> immunodeficient murine model.</p><p><b>Results:</b> PD-1 is consistently expressed on a small subset of melanoma cells, but PD-1<sup>+</sup> cells increase to relevant rates during BRAF/MEKi treatment [7.3% (5.6–14.2) vs. 1.5% (0.7–3.2), <i>P</i> = 0.0156; <i>N</i> = 7], together with PD-L2<sup>+</sup> melanoma cells [8.5% (0.0–63.0) vs. 1.5% (0.2–43.3), <i>P</i> = 0.0312; <i>N</i> = 7]. PD-1<sup>+</sup> cells proliferate less than PD-1<sup>−</sup> cells (avg. 65% less; <i>t</i> = 7 days) and are preferentially endowed with stemness features. <i>In vivo</i>, 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.</p><p><b>Conclusions:</b> BRAF/MEKi increase the rates of PD-1<sup>+</sup> melanoma cells that may sustain tumor relapse, providing a lymphocyte-independent rationale to explore combinatory strategies with anti–PD-1 antibody. <i>Clin Cancer Res; 24(14); 3377–85. ©2018 AACR</i>.</p></div>
<p>Fig. S4. PD1+ melanoma cells proliferate less than their PD1- counterpart. A representative proliferation assay is shown. The proliferation of PD1+ and PD1- mMel2 patient-derived melanoma cells was evaluated by the vital dye CFSE staining and fluorescence intensity decrement over time.</p>
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