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posted on 2023-04-03, 23:06 authored by Antoni Ribas, Daniel Sanghoon Shin, Jesse Zaretsky, Juliet Frederiksen, Andrew Cornish, Earl Avramis, Elizabeth Seja, Christine Kivork, Janet Siebert, Paula Kaplan-Lefko, Xiaoyan Wang, Bartosz Chmielowski, John A. Glaspy, Paul C. Tumeh, Thinle Chodon, Dana Pe'er, Begoña Comin-Anduix Activation status of T and B cells. (A) T cell gating strategy. T cells from Fig. S1, were split into CD4+ and CD4- (CD8+) T subsets, and subsequently analyzed for the activation markers CD25 and HLA-DR. (B) Percentage of activated CD4+ and CD8 (CD4-) T cell subsets. (C) B cell gating strategy. From B cells, the activation marker HLA-DR (black box) was quantified. (D) Percentage of activated B cells on therapy. Biexponential displaying was done for the dot plots. Mean and {plus minus} SD are provided. B = before treatment; P = on anti-PD-1 therapy; n = number of biopsies analyzed. Solid circles represent responders; open circles represent non-responders (n= 26 baseline; n= 22 on therapy).
Funding
NIH, Cancer Research Institute and Cancer Immunology Dream Team Translational Research
Cancer Phillip A. Sharp Innovation
Tower Cancer Research Foundation
NIH and JCCC, JCCC, the UCLA AIDS Institute, and the David Geffen School of Medicine at UCLA
History
ARTICLE ABSTRACT
Tumor responses to programmed cell death protein 1 (PD-1) blockade therapy are mediated by T cells, which we characterized in 102 tumor biopsies obtained from 53 patients treated with pembrolizumab, an antibody to PD-1. Biopsies were dissociated, and single-cell infiltrates were analyzed by multicolor flow cytometry using two computational approaches to resolve the leukocyte phenotypes at the single-cell level. There was a statistically significant increase in the frequency of T cells in patients who responded to therapy. The frequency of intratumoral B cells and monocytic myeloid-derived suppressor cells significantly increased in patients' biopsies taken on treatment. The percentage of cells with a regulatory T-cell phenotype, monocytes, and natural killer cells did not change while on PD-1 blockade therapy. CD8+ memory T cells were the most prominent phenotype that expanded intratumorally on therapy. However, the frequency of CD4+ effector memory T cells significantly decreased on treatment, whereas CD4+ effector T cells significantly increased in nonresponding tumors on therapy. In peripheral blood, an unusual population of blood cells expressing CD56 was detected in two patients with regressing melanoma. In conclusion, PD-1 blockade increases the frequency of T cells, B cells, and myeloid-derived suppressor cells in tumors, with the CD8+ effector memory T-cell subset being the major T-cell phenotype expanded in patients with a response to therapy. Cancer Immunol Res; 4(3); 194–203. ©2016 AACR.
