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

Abstract

<div>AbstractPurpose:<p>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.</p>Experimental Design:<p>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.</p>Results:<p>mIHC demonstrated fewer CD8<sup>+</sup> 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<sup>+</sup> T-cell migration into the juxtatumoral compartment and rapid increase in tumor cell apoptosis.</p>Conclusions:<p>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.</p><p><i>See related commentary by Medina and Miller, p. 3747</i></p></div>