期刊
CLINICAL CANCER RESEARCH
卷 25, 期 13, 页码 3934-3945出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-19-0081
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资金
- NIH [S10 OD016240]
- Parvin Valentini Fund for Pancreatic Cancer Research
- Donald E. Bocek Endowed Research Development Award in Pancreatic Cancer
- United States Army Medical Research Acquisition Activity (USAMRAA) [CA150370P2]
- Swim Across America
- Merck Investigator Studies Program
- Seattle Foundation
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.
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