title: Impact of diffusion barriers to small cytotoxic molecules on the efficacy of immunotherapy in breast cancer.
abstract: 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 γδ T-cell scarcity in tissue to limit the inhibitory effects of γδ T-cells on cancer cells. This may increase the necessary ratios of γδ T-cells to cancer cells within tissue to unrealistic values for having an intended therapeutic effect, and decrease the effectiveness of the immunotherapeutic treatment.
authors.affiliation: Department of Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA. hiranmoy.das@osumc.edu
authors.forename: Hiranmoy
authors.initials: H
authors.lastname: Das
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Wang
authors.forename: M Khalid Khan
authors.initials: MK
authors.lastname: Niazi
authors.forename: Reeva
authors.initials: R
authors.lastname: Aggarwal
authors.forename: Jingwei
authors.initials: J
authors.lastname: Lu
authors.forename: Suman
authors.initials: S
authors.lastname: Kanji
authors.forename: Manjusri
authors.initials: M
authors.lastname: Das
authors.forename: Matthew
authors.initials: M
authors.lastname: Joseph
authors.forename: Metin
authors.initials: M
authors.lastname: Gurcan
authors.forename: Vittorio
authors.initials: V
authors.lastname: Cristini
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D002450:Cell Communication; D045744:Cell Line, Tumor; D002470:Cell Survival; D004058:Diffusion; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D016692:Receptors, Antigen, T-Cell, gamma-delta; D007371:Interferon-gamma