Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrence.
Tumor recurrence represents a major clinical challenge. Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors. This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence. Screening for this innate response predicted accurately in which mice recurrence would occur. Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete. By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured. These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment.
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Timothy
T
Kottke
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Nicolas
N
Boisgerault
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Rosa Maria
RM
Diaz
Cancer Research UK Centre, St. James's University Hospital, Leeds, UK.
Oliver
O
Donnelly
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Diana
D
Rommelfanger-Konkol
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Department of Ophthalmology and Ocular Oncology, Mayo Clinic, Rochester, Minnesota, USA.
Jose
J
Pulido
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Jill
J
Thompson
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.
Debabrata
D
Mukhopadhyay
TransDerm, Santa Cruz, California, USA.
Roger
R
Kaspar
Oncolytics Biotech, Calgary, Alberta, Canada.
Matt
M
Coffey
Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
Hardev
H
Pandha
Cancer Research UK Centre, St. James's University Hospital, Leeds, UK.
Alan
A
Melcher
The Institute of Cancer Research, London, UK.
Kevin
K
Harrington
Cancer Research UK Centre, St. James's University Hospital, Leeds, UK.
Peter
P
Selby
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Cancer Research UK Centre, St. James's University Hospital, Leeds, UK.|Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
Richard
R
Vile
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D055088:Early Detection of Cancer / Q000379:methods; D005260:Female; D007113:Immunity, Innate / Q000502:physiology*; D008546:Melanoma, Experimental / Q000175:diagnosis* / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000188:drug therapy / Q000276:immunology; D018365:Neoplasm, Residual; D012878:Skin Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000502:physiology*