Mobilization of CD8 + T Cells via CXCR4 Blockade Facilitates PD-1 Checkpoint Therapy in Human Pancreatic Cancer.

Autor:	Seo YD; Department of Surgery, University of Washington, Seattle, Washington., Jiang X; Department of Surgery, University of Washington, Seattle, Washington., Sullivan KM; Department of Surgery, University of Washington, Seattle, Washington., Jalikis FG; Department of Pathology, University of Washington, Seattle, Washington., Smythe KS; Fred Hutchinson Cancer Research Center, Seattle, Washington., Abbasi A; Department of Surgery, University of Washington, Seattle, Washington., Vignali M; Adaptive Biotechnologies, Seattle, Washington., Park JO; Department of Surgery, University of Washington, Seattle, Washington., Daniel SK; Department of Surgery, University of Washington, Seattle, Washington., Pollack SM; Fred Hutchinson Cancer Research Center, Seattle, Washington., Kim TS; Department of Surgery, University of Washington, Seattle, Washington., Yeung R; Department of Surgery, University of Washington, Seattle, Washington., Crispe IN; Department of Pathology, University of Washington, Seattle, Washington., Pierce RH; Fred Hutchinson Cancer Research Center, Seattle, Washington., Robins H; Fred Hutchinson Cancer Research Center, Seattle, Washington.; Adaptive Biotechnologies, Seattle, Washington., Pillarisetty VG; Department of Surgery, University of Washington, Seattle, Washington. vgp@uw.edu.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Jul 01; Vol. 25 (13), pp. 3934-3945. Date of Electronic Publication: 2019 Apr 02.
DOI:	10.1158/1078-0432.CCR-19-0081
Abstrakt:	Purpose: Pancreatic ductal adenocarcinoma (PDA) is rarely cured, and single-agent immune checkpoint inhibition has not demonstrated clinical benefit despite the presence of large numbers of CD8 + T cells. We hypothesized that tumor-infiltrating CD8 + T cells harbor latent antitumor activity that can be reactivated using combination immunotherapy. Experimental Design: Preserved human PDA specimens were analyzed using multiplex IHC (mIHC) and T-cell receptor (TCR) sequencing. Fresh tumor was treated in organotypic slice culture to test the effects of combination PD-1 and CXCR4 blockade. Slices were analyzed using IHC, flow cytometry, and live fluorescent microscopy to assess tumor kill, in addition to T-cell expansion and mobilization. Results: mIHC demonstrated fewer CD8 + T cells in juxtatumoral stroma containing carcinoma cells than in stroma devoid of them. Using TCR sequencing, we found clonal expansion in each tumor; high-frequency clones had multiple DNA rearrangements coding for the same amino acid binding sequence, which suggests response to common tumor antigens. Treatment of fresh human PDA slices with combination PD-1 and CXCR4 blockade led to increased tumor cell death concomitant with lymphocyte expansion. Live microscopy after combination therapy demonstrated CD8 + T-cell migration into the juxtatumoral compartment and rapid increase in tumor cell apoptosis. Conclusions: Endogenous tumor-reactive T cells are present within the human PDA tumor microenvironment and can be reactivated by combined blockade of PD-1 and CXCR4. This provides a new basis for the rational selection of combination immunotherapy for PDA. See related commentary by Medina and Miller, p. 3747 . (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu