Mobilization of CD8+ T cells via CXCR4 blockade facilitates PD-1 checkpoint therapy in human pancreatic cancer

Yongwoo David Seo, Xiuyun Jiang, Kevin M. Sullivan, Florencia G. Jalikis, Kimberly S. Smythe, Arezou Abbasi, Marissa Vignali, James O. Park, Sara K. Daniel, Seth M. Pollack, Teresa S. Kim, Raymond Yeung, Ian Nicholas Crispe, Robert H. Pierce, Harlan Robins, Venu G. Pillarisetty*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

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 tumorinfiltrating 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 multipleDNArearrangements 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.

Original languageEnglish (US)
Pages (from-to)3934-3945
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number13
DOIs
StatePublished - 2019
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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