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Tietze, Julia K.; Angelova, Daniela; Heppt, Markus V.; Reinholz, Markus; Murphy, William J.; Spannagl, Michäl; Ruzicka, Thomas; Berking, Carola (2017): The proportion of circulating CD45RO(+)CD8(+) memory T cells is correlated with clinical response in melanoma patients treated with ipilimumab. In: European Journal of Cancer, Vol. 75: S. 268-279
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Abstract

Background: Immune checkpoint blockade (ICB) has been a breakthrough in the treatment of metastatic melanoma. But with only about 20-40% long-term responders and severe side-effects in about 12-17%, finding predictive markers for treatment response is of great interest. Methods: We prospectively assessed clinical data, haematologic parameters and freshly isolated peripheral.blood mononuclear cells of 30 patients treated with ipilimumab (n = 21) and pembrolizumab (n = 9) prior to the first 4 cycles with ICB and before the first tumour assessment. Results: We discovered that the baseline levels of CD45RO(+)CD8(+) T cells significantly differed among the patients. Thirteen (43%) of our patients had normal baseline levels of CD45RO(+)CD8(+) T cells, whereas 17 (57%) patients were low on CD45RO(+)CD8(+) T cells. The baseline levels of CD45RO(+)CD8(+) T cells correlated significantly with the response to ipilimumab but not pembrolizumab. Patients with baseline levels of lower/equal 25% of CD45RO(+)CD8(+) T cells did not respond to treatment with ipilimumab. Phenotyping the CD8(+) T cells in patients treated with ipilimumab revealed an activated HLA-DR(+)CD25(-) phenotype, implying antigen non-specific stimulation. The levels of the HLA-DR(+)CD25(-) CD8(+) T cells were significantly higher in patients with a normal baseline of CD45RO(+)CD8(+) T cells and even increased significantly during treatment. Furthermore, proliferation of melanoma antigen recognized by T cells 1 (MART-1)-specific CD8(+) T cells was not observed. Patients with normal baseline levels of CD45RO(+)CD8(+) T cells showed a significant longer overall survival when treated with ipilimumab but not pembrolizumab. Conclusion: Patients with normal baseline levels of CD45RO(+)CD8(+) T cells respond significantly more frequently to treatment with ipilimumab and the CD8(+) T cells appear to be antigen non-specifically activated. The baseline level of CD45RO(+)CD8(+) T cells represents a promising factor as biomarker for the prediction of the response to ipilimumab.