Journal
PLOS ONE
Volume 8, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0061398
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Categories
Funding
- National Cancer Institute [CTO PSOC - 1U54CA143837, TCCN - 1U54CA151668, USC PSOC - 1U54CA143907, ICBP - 1U54CA149196]
- National Institutes of Health [K01 AR054114, SBIR R44 HL092706-01]
- Ohio State University
- NCI [R01CA134451]
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Molecular-focused cancer therapies, e. g., molecularly targeted therapy and immunotherapy, so far demonstrate only limited efficacy in cancer patients. We hypothesize that underestimating the role of biophysical factors that impact the delivery of drugs or cytotoxic cells to the target sites (for associated preferential cytotoxicity or cell signaling modulation) may be responsible for the poor clinical outcome. Therefore, instead of focusing exclusively on the investigation of molecular mechanisms in cancer cells, convection-diffusion of cytotoxic molecules and migration of cancer-killing cells within tumor tissue should be taken into account to improve therapeutic effectiveness. To test this hypothesis, we have developed a mathematical model of the interstitial diffusion and uptake of small cytotoxic molecules secreted by T-cells, which is capable of predicting breast cancer growth inhibition as measured both in vitro and in vivo. Our analysis shows that diffusion barriers of cytotoxic molecules conspire with gamma delta T-cell scarcity in tissue to limit the inhibitory effects of gamma delta T-cells on cancer cells. This may increase the necessary ratios of gamma delta T-cells to cancer cells within tissue to unrealistic values for having an intended therapeutic effect, and decrease the effectiveness of the immunotherapeutic treatment.
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