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Immuno-PET identifies the myeloid compartment as a key contributor to the outcome of the antitumor response under PD-1 blockade.
Rashidian, Mohammad; LaFleur, Martin W; Verschoor, Vincent L; Dongre, Anushka; Zhang, Yun; Nguyen, Thao H; Kolifrath, Stephen; Aref, Amir R; Lau, Christie J; Paweletz, Cloud P; Bu, Xia; Freeman, Gordon J; Barrasa, M Inmaculada; Weinberg, Robert A; Sharpe, Arlene H; Ploegh, Hidde L.
Afiliação
  • Rashidian M; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
  • LaFleur MW; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
  • Verschoor VL; Department of Imaging, Dana-Farber Cancer Institute, Boston, MA 02215.
  • Dongre A; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115.
  • Zhang Y; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
  • Nguyen TH; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
  • Kolifrath S; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
  • Aref AR; Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
  • Lau CJ; Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
  • Paweletz CP; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115.
  • Bu X; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
  • Freeman GJ; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
  • Barrasa MI; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
  • Weinberg RA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.
  • Sharpe AH; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215.
  • Ploegh HL; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215.
Proc Natl Acad Sci U S A ; 116(34): 16971-16980, 2019 08 20.
Article em En | MEDLINE | ID: mdl-31375632
Immunotherapy using checkpoint-blocking antibodies against PD-1 has produced impressive results in a wide range of cancers. However, the response remains heterogeneous among patients. We used noninvasive immuno-positron emission tomography (PET), using 89Zr-labeled PEGylated single-domain antibody fragments (nanobodies or VHHs), to explore the dynamics and distribution of intratumoral CD8+ T cells and CD11b+ myeloid cells in response to anti-PD-1 treatment in the MC38 colorectal mouse adenocarcinoma model. Responding and nonresponding tumors showed consistent differences in the distribution of CD8+ and CD11b+ cells. Anti-PD-1 treatment mobilized CD8+ T cells from the tumor periphery to a more central location. Only those tumors fully infiltrated by CD8+ T cells went on to complete resolution. All tumors contained CD11b+ myeloid cells from the outset of treatment, with later recruitment of additional CD11b+ cells. As tumors grew, the distribution of intratumoral CD11b+ cells became more heterogeneous. Shrinkage of tumors in responders correlated with an increase in the CD11b+ population in the center of the tumors. The changes in distribution of CD8+ and CD11b+ cells, as assessed by PET, served as biomarkers to gauge the efficacy of anti-PD-1 treatment. Single-cell RNA sequencing of RNA from intratumoral CD45+ cells showed that CD11b+ cells in responders and nonresponders were markedly different. The responders exhibited a dominant population of macrophages with an M1-like signature, while the CD45+ population in the nonresponders displayed an M2-like transcriptional signature. Thus, by using immuno-PET and single-cell RNA sequencing, we show that anti-PD-1 treatment not only affects interactions of CD8+ T cells with the tumor but also impacts the intratumoral myeloid compartment.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Adenocarcinoma / Linfócitos T CD8-Positivos / Tomografia por Emissão de Pósitrons / Receptor de Morte Celular Programada 1 / Antígenos de Neoplasias / Proteínas de Neoplasias / Neoplasias Experimentais Limite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Adenocarcinoma / Linfócitos T CD8-Positivos / Tomografia por Emissão de Pósitrons / Receptor de Morte Celular Programada 1 / Antígenos de Neoplasias / Proteínas de Neoplasias / Neoplasias Experimentais Limite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2019 Tipo de documento: Article