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Cancer Immunol Res. 2019 Jun;7(6):977-989. doi: 10.1158/2326-6066.CIR-18-0448. Epub 2019 Apr 26.

Differential Effects of Depleting versus Programming Tumor-Associated Macrophages on Engineered T Cells in Pancreatic Ductal Adenocarcinoma.

Author information

1
Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota. ingunn@umn.edu pgreen@uw.edu srh@fhcrc.org.
2
Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota.
3
Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota.
4
Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota.
5
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
6
Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
7
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. ingunn@umn.edu pgreen@uw.edu srh@fhcrc.org.
8
Division of Medical Oncology, University of Washington School of Medicine, Seattle, Washington.
9
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy resistant to therapies, including immune-checkpoint blockade. We investigated two distinct strategies to modulate tumor-associated macrophages (TAM) to enhance cellular therapy targeting mesothelin in an autochthonous PDA mouse model. Administration of an antibody to colony-stimulating factor (anti-Csf1R) depleted Ly6Clow protumorigenic TAMs and significantly enhanced endogenous T-cell intratumoral accumulation. Despite increasing the number of endogenous T cells at the tumor site, as previously reported, TAM depletion had only minimal impact on intratumoral accumulation and persistence of T cells engineered to express a murine mesothelin-specific T-cell receptor (TCR). TAM depletion interfered with the antitumor activity of the infused T cells in PDA, evidenced by reduced tumor cell apoptosis. In contrast, TAM programming with agonistic anti-CD40 increased both Ly6Chigh TAMs and the intratumoral accumulation and longevity of TCR-engineered T cells. Anti-CD40 significantly increased the frequency and number of proliferating and granzyme B+ engineered T cells, and increased tumor cell apoptosis. However, anti-CD40 failed to rescue intratumoral engineered T-cell IFNγ production. Thus, although functional modulation, rather than TAM depletion, enhanced the longevity of engineered T cells and increased tumor cell apoptosis, ultimately, anti-CD40 modulation was insufficient to rescue key effector defects in tumor-reactive T cells. This study highlights critical distinctions between how endogenous T cells that evolve in vivo, and engineered T cells with previously acquired effector activity, respond to modifications of the tumor microenvironment.

PMID:
31028033
PMCID:
PMC6548612
[Available on 2020-06-01]
DOI:
10.1158/2326-6066.CIR-18-0448

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