Response to programmed cell death-1 blockade in a murine melanoma syngeneic model requires costimulation, CD4, and CD8 T cells

Blanca Homet Moreno, Jesse M. Zaretsky, Angel Garcia-Diaz, Jennifer Tsoi, Giulia Parisi, Lidia Robert, Katrina Meeth, Abibatou Ndoye, Marcus Bosenberg, Ashani T. Weeraratna, Thomas G. Graeber, Begoña Comin-Anduix, Siwen Hu-Lieskovan, Antoni Ribas

Research output: Contribution to journalArticle

Abstract

The programmed cell death protein 1 (PD-1) limits effector T-cell functions in peripheral tissues, and its inhibition leads to clinical benefit in different cancers. To better understand how PD-1 blockade therapy modulates the tumor-host interactions, we evaluated three syngeneic murine tumor models, the BRAFV600E-driven YUMM1.1 and YUMM2.1 melanomas, and the carcinogen-induced murine colon adenocarcinoma MC38. The YUMM cell lines were established from mice with melanocyte-specific BRAFV600E mutation and PTEN loss (BRAFV600E/PTEN-/-). Anti-PD-1 or anti-PD-L1 therapy engendered strong antitumor activity against MC38 and YUMM2.1, but not YUMM1.1. PD-L1 expression did not differ between the three models at baseline or upon interferon stimulation. Whereas mutational load was high in MC38, it was lower in both YUMM models. In YUMM2.1, the antitumor activity of PD-1 blockade had a critical requirement forboth CD4 and CD8 Tcells, as well as CD28 and CD80/86 costimulation, with an increase in CD11c+ CD11b+MHC-IIhigh dendritic cells and tumor-associated macrophages in the tumors after PD-1 blockade. Compared with YUMM1.1, YUMM2.1 exhibited a more inflammatory profile by RNA sequencing analysis, with an increase in expression of chemokine-trafficking genes that are related to immune cell recruitment and T-cell priming. In conclusion, response to PD-1 blockade therapy in tumor models requires CD4 and CD8 T cells and costimulation that is mediated by dendritic cells and macrophages.

Original languageEnglish (US)
Pages (from-to)845-857
Number of pages13
JournalCancer Immunology Research
Volume4
Issue number10
DOIs
StatePublished - Oct 2016

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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    Moreno, B. H., Zaretsky, J. M., Garcia-Diaz, A., Tsoi, J., Parisi, G., Robert, L., Meeth, K., Ndoye, A., Bosenberg, M., Weeraratna, A. T., Graeber, T. G., Comin-Anduix, B., Hu-Lieskovan, S., & Ribas, A. (2016). Response to programmed cell death-1 blockade in a murine melanoma syngeneic model requires costimulation, CD4, and CD8 T cells. Cancer Immunology Research, 4(10), 845-857. https://doi.org/10.1158/2326-6066.CIR-16-0060