Serum biomarkers which correlate with failure to respond to immunotherapy and tumor progression in a murine colorectal cancer model.
OBJECTIVE
To advance our understanding of mechanisms involved in tumor progression/regression, a CT26 colorectal mouse model treated intra-tumorally with DISC-herpes simplex virus as immunotherapy was used in the discovery and validation phases to investigate and ultimately identify biomarkers correlating with the failure to respond to immunotherapy.


METHODS
For the discovery phase, serum protein/peptide profiles of a retrospective sample collection (total n=70) were analyzed using MALDI-TOF-MS combined with artificial neural networks. Following identification of the key predictive peptides using ESI-MS/MS, validation of the identified proteins was carried out on serum and tissues collected in an independent sample set (total n=60).


RESULTS
Artificial neural network analysis resulted in four discriminatory peaks with an accuracy of 86%, sensitivity of 90% and specificity of 81% between the progressor/regressor groups. Three of the identified discriminatory markers were upregulated and demonstrated a positive correlation with tumor progression following DISC-herpes simplex virus therapy. Immunovalidation studies corroborated the MALDI-TOF-MS findings. Immunohistochemistry revealed that serum amyloid A-1 and serum amyloid P produced in the liver localized intracellularly in CT26 tumor tissue.


CONCLUSIONS
MALDI-TOF-MS and BI analysis of the serum proteome of tumor-bearer mice undergoing immunotherapy, identified biomarkers associating with "failure to respond" and biological arrays confirmed these findings.
The John Van Geest Cancer Research Centre, Nottingham Trent University, School of Science and Technology, Clifton Lane, Nottingham, UK.
Baharak
B
Vafadar-Isfahani
Stephanie Anne-Sophie
SA
Laversin
Murrium
M
Ahmad
Graham
G
Ball
Clare
C
Coveney
Christophe
C
Lemetre
Amanda
A
Kathleen Miles
Gerhard
G
van Schalkwyk
Robert
R
Rees
Balwir
B
Matharoo-Ball
D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood*; D015179:Colorectal Neoplasms / Q000097:blood* / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009367:Neoplasm Staging / Q000379:methods*; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D016896:Treatment Outcome
D014408:Biomarkers, Tumor