Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake.
Tumor-associated fibroblasts are key regulators of tumorigenesis. In contrast to tumor cells, which are genetically unstable and mutate frequently, the presence of genetically more stable fibroblasts in the tumor-stromal compartment makes them an optimal target for cancer immunotherapy. These cells are also the primary source of collagen type I, which contributes to decreased chemotherapeutic drug uptake in tumors and plays a significant role in regulating tumor sensitivity to a variety of chemotherapies. To specifically kill tumor-associated fibroblasts, we constructed an oral DNA vaccine targeting fibroblast activation protein (FAP), which is specifically overexpressed by fibroblasts in the tumor stroma. Through CD8+ T cell-mediated killing of tumor-associated fibroblasts, our vaccine successfully suppressed primary tumor cell growth and metastasis of multidrug-resistant murine colon and breast carcinoma. Furthermore, tumor tissue of FAP-vaccinated mice revealed markedly decreased collagen type I expression and up to 70% greater uptake of chemotherapeutic drugs. Most importantly, pFap-vaccinated mice treated with chemotherapy showed a 3-fold prolongation in lifespan and marked suppression of tumor growth, with 50% of the animals completely rejecting a tumor cell challenge. This strategy opens a new venue for the combination of immuno- and chemotherapies.
Loeffler
Markus
M
The Scripps Research Institute, Department of Immunology, La Jolla, California 92037, USA, and Department of Radiation Oncology, Heidelberg Medical School, Heidelberg, Germany.
Krüger
Jörg A
JA
Niethammer
Andreas G
AG
Reisfeld
Ralph A
RA
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D010450:Endopeptidases; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D015996:Survival Rate; D019444:Vaccines, DNA; D000099167:Fibroblast Activation Protein Alpha
D019496:Cancer Vaccines; D024042:Collagen Type I; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; D012697:Serine Endopeptidases; D019444:Vaccines, DNA; D000099167:Fibroblast Activation Protein Alpha