Metronomic cyclophosphamide activation of anti-tumor immunity: tumor model, mouse host, and drug schedule dependence of gene responses and their upstream regulators.

Abstract

BACKGROUND:

Cyclophosphamide (CPA) can activate immunogenic tumor cell death, which induces immune-based tumor ablation and long-term anti-tumor immunity in a syngeneic C57BL/6 (B6) mouse GL261 glioma model when CPA is given on a 6-day repeating metronomic schedule (CPA/6d). In contrast, we find that two other syngeneic B6 mouse tumors, LLC lung carcinoma and B16F10 melanoma, do not exhibit these drug-induced immune responses despite their intrinsic sensitivity to CPA cytotoxicity.

METHODS:

To elucidate underlying mechanisms, we investigated gene expression and molecular pathway changes associated with the disparate immune responsiveness of these tumors to CPA/6d treatment.

RESULTS:

Global transcriptome analysis indicated substantial elevation of basal GL261 immune infiltration and strong CPA/6d activation of GL261 immune stimulatory pathways and their upstream regulators, but without preferential depletion of negative immune regulators compared to LLC and B16F10 tumors. In LLC tumors, where CPA/6d treatment is shown to be anti-angiogenic, CPA/6d suppressed VEGFA target genes and down regulated cell adhesion and leukocyte transendothelial migration genes. In GL261 tumors implanted in adaptive immune-deficient scid mice, where CPA/6d-induced GL261 regression is incomplete and late tumor growth rebound can occur, T cell receptor signaling and certain cytokine-cytokine receptor responses seen in B6 mice were deficient. Extending the CPA treatment interval from 6 to 9 days (CPA/9d) - which results in a strong but transient natural killer cell response followed by early tumor growth rebound - induced fewer cytokines and increased expression of drug metabolism genes.

CONCLUSIONS:

These findings elucidate molecular response pathways activated by intermittent metronomic CPA treatment and identify deficiencies that characterize immune-unresponsive tumor models and drug schedules.

• Authors: Junjie Wu, Marie Jordan, David J Waxman
• Journal: BMC cancer (BMC Cancer) Vol. 16 Pg. 623 (08 11 2016) ISSN: 1471-2407 [Electronic] England
• PMID: 27515027 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adjuvants, Immunologic
• Antineoplastic Agents, Alkylating
• Cyclophosphamide

Topics

• Adjuvants, Immunologic (administration & dosage)
• Administration, Metronomic
• Animals
• Antineoplastic Agents, Alkylating (administration & dosage)
• Brain Neoplasms (drug therapy, immunology, metabolism)
• Cell Line, Tumor
• Cyclophosphamide (administration & dosage)
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Female
• Gene Expression (drug effects)
• Glioma (drug therapy, immunology, metabolism)
• Immunity, Innate (drug effects)
• Male
• Mice, Inbred C57BL
• Mice, SCID
• Neoplasm Transplantation
• Promoter Regions, Genetic