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Surgical Innovation
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Perioperative Immunomodulation With Flt3 Kinase Ligand or a Whole Tumor Cell Vaccine Is Associated With a Reduction in Lung Metastasis Formation After Laparotomy in Mice

Joseph J. Carter, MD

Laparoscopic Physiology Laboratory, Department of Surgery, College of Physician and Surgeons, Columbia University, New York, NY; Bellevue Hospital, 27th Street and 1st Avenue, Suite 15 South-14, New York, NY 10016 cartej08{at}med.nyu.edu

Daniel L. Feingold, MD

Anthony Oh, MD

Irena Kirman, MD, PhD

Peer Wildbrett, BS

George Stapleton, BS

Zishan Asi, BA

Ryan Fowler, BS

Govind Bhagat, MD

Emina H. Huang, MD

Robert L. Fine, MD

Richard L. Whelan, MD

Laparoscopic Physiology Laboratory, Department of Surgery, College of Physician and Surgeons, Columbia University, New York, NY

Introduction:Laparotomy has been associated with temporary postoperative immunosuppression and accelerated tumor growth in experimental models. In a previous murine study, a whole cell vaccine plus the adjuvant monophosphoryl-lipid A was shown to be effective in decreasing the number of lung metastases that develop after laparotomy. This study was conducted to assess the impact of the adjuvant fetal liver tyrosine kinase 3 (Flt3) ligand on perioperative tumor growth when used alone or with a tumor cell vaccine.

Methods:An intravenous tumor cell injection lung metastases model was used. Sixty female A/J mice were divided into six equal groups designated (1) anesthesia control (AC), (2) AC with Flt3 ligand (ACFlt3), (3) sham laparotomy (OP), (4) OP with Flt3 ligand (OPFlt3), (5) OP with vaccine (OPVac), and (6) OP with Flt3 ligand and vaccine (OPFlt3Vac). Groups 2, 4, and 6 received daily intraperitoneal injections of Flt3 ligand (10µg/dose with carrier) for 5 days before and 5 days after surgery. Groups 1 and 3 received similar injections of saline on the same schedule. Groups 5 and 6 were vaccinated with irradiated whole Ta3Ha tumor cells intraperitoneally three times before and twice after surgery. Immediately after surgery, all mice were injected with 105 Ta3Ha tumor cells via a tail vein. After 14 days, the mice were sacrificed and their lungs and tracheas were excised en bloc. Specimens were stained and counterstained with India ink and Fekete solution, and surface metastases were counted by a blinded observer. Differences between study groups were determined by analysis of variance. The peritumoral inflammatory cell infiltrate of some Flt3 and control specimens was also assessed.

Results:Regarding laparotomy, Flt3 ligand (mean, 1.22 metastases), whole cell vaccine (1.12 metastases), and the combination of these two agents (0.1 metastases) were each effective in significantly decreasing the number of surface lung metastases compared with surgery alone (9.88 metastases, P < .05 for all comparisons). There were no differences between the various treatment groups in regards to number of metastases. Only the combination of Flt3 and the vaccine significantly lowered the incidence of tumors (number of mice with>1 tumors). Histologic analysis revealed that the Flt3-treated mice demonstrated increased numbers of antigen-presenting cells surrounding the tumors compared with controls.

Conclusions: Perioperative treatment with either Flt3 ligand or a whole cell tumor vaccine significantly reduced the number of lung metastases after laparotomy. The combination of the Flt3 ligand and the vaccine also decreased the incidence of metastases and was the most effective treatment. Further studies regarding perioperative immune modulation in the setting of cancer appear warranted.

Key Words: cancer • metastases • Flt3 ligand • immunotherapy • vaccine

References

Surgical Innovation, Vol. 13, No. 1, 41-47 (2006)
DOI: 10.1177/155335060601300107
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This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via Web of Science (1)
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Carter, J. J.
Right arrow Articles by Whelan, R. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Carter, J. J.
Right arrow Articles by Whelan, R. L.
Social Bookmarking
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