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


ABSTRACT: 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.

SUBMITTER: Seo YD 

PROVIDER: S-EPMC6606359 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Seo Yongwoo David YD   Jiang Xiuyun X   Sullivan Kevin M KM   Jalikis Florencia G FG   Smythe Kimberly S KS   Abbasi Arezou A   Vignali Marissa M   Park James O JO   Daniel Sara K SK   Pollack Seth M SM   Kim Teresa S TS   Yeung Raymond R   Crispe Ian Nicholas IN   Pierce Robert H RH   Robins Harlan H   Pillarisetty Venu G VG  

Clinical cancer research : an official journal of the American Association for Cancer Research 20190402 13


<h4>Purpose</h4>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<sup>+</sup> T cells. We hypothesized that tumor-infiltrating CD8<sup>+</sup> T cells harbor latent antitumor activity that can be reactivated using combination immunotherapy.<h4>Experimental design</h4>Preserved human PDA specimens were analyzed using multiplex IHC (mIHC) and T-cell receptor (TCR)  ...[more]

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