Inhibition of Interleukin-10 in the tumor microenvironment can restore mesothelin chimeric antigen receptor T cell activity in pancreatic cancer in vitro
Section snippets
Cell lines and conditioned medium
We tested 4 human PC cell lines for mesothelin expression (BxPC-3, Capan-1, PANC-1, and MIA PaCa-2), all of which were positive. Although all were positive, BxPC-3 had the greatest expression and was the only nonmetastatic cell line. Because cancer cell lines derived from earlier-stage and lower-grade disease are better models in which to study the effects of novel therapies and establish proof of principle,15 we chose not to include metastatic tumor cell lines in this initial study and could
Efficiency of CAR engraftment of T cells and lentiviral transduction
Third-generation, mesothelin-CAR vector was constructed using cell-surface scFv linked to the CD8α hinge and transmembrane region. This was connected intracellularly with the cytoplasmic portion of two costimulatory domains, CD28 and 4-1BB (CD137), as well as an activation domain derived from the cytoplasmic part of CD3ζ (Fig 1, A). The CAR construct was incorporated into lentiviral vectors driven by the promoter for elongation factor 1 alpha (EF1α), which is preferable for expression in T
Discussion
The PC microenvironment represents an immunosuppressed state, particularly in the more advanced stages of the disease, because tumor cells in vivo secrete spontaneously protective anti-inflammatory cytokines, such as TGF-β and IL-10, that can specifically defend against immune attack.13 Use of mesothelin-engrafted CAR T cells for PC immunotherapy is an active area of research,12, 19, 20 but immune inhibitory mechanisms often observed in solid tumors, which may compromise the efficacy of
References (25)
- et al.
Role of the immune system in pancreatic cancer progression and immune modulating treatment strategies
Cancer Treat Rev
(2014) - et al.
Redirected antitumor activity of primary human lymphocytes transduced with a fully human anti-mesothelin chimeric receptor
Mol Ther
(2012) - et al.
Preclinical mouse cancer models: a maze of opportunities and challenges
Cell
(2015) - et al.
Perioperative treatment options in resectable pancreatic cancer—how to improve long-term survival
World J Gastrointest Oncol
(2016) - et al.
Metastatic pancreatic tumors: what is the optimal treatment?
Minerva Chir
(2015) - et al.
T-cell programming in pancreatic adenocarcinoma: a review
Cancer Gene Ther
(2017) - et al.
CAR T cell therapy: a game changer in cancer treatment
J Immunol Res
(2016) - et al.
Building better chimeric antigen receptors for adoptive T cell therapy
Curr Gene Ther
(2010) - et al.
Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors
Proc Natl Acad Sci USA
(1993) Immunotherapy of malignant disease using chimeric antigen receptor engrafted T cells
ISRN Oncol
(2012)
Functional deficiencies of components of the MHC class I antigen pathway in human tumors of epithelial origin
Bone Marrow Transplant
Expansion of anti-mesothelin specific CD4+ and CD8+ T cell responses in patients with pancreatic carcinoma
PLoS ONE
Cited by (0)
Supported in part by grants from the Michael and Marian Ilitch Foundation and the Detroit International Research and Education Foundation.
Presented at the Central Surgical Association and Midwest Surgical Association Combined Annual Meeting, July 30-August 1, 2017, Chicago, IL.