Intratumoral T cell infiltration, MHC class I and STAT1 as biomarkers of good prognosis in colorectal cancer.
OBJECTIVE
To evaluate immunosurveillance/editing in colorectal cancer.


METHODS
Transformation stimulates the production of interferon gamma (IFNgamma) which signals via the IFNgamma receptor (IFNGR1) on tumours. This results in stimulation of nuclear STAT1 (nSTAT1), inhibition of tumour growth and upregulation of major histocompatibility complex (MHC) while promoting T cell extravasation. In contrast, downregulation of MHC class I by allele loss results in loss of T cell recognition. A tissue microarray of 462 colorectal tumours with mean follow-up of 42 months (range 1-116) was stained by immunohistochemistry for markers which predict immunosurveillance/editing.


RESULTS
The presence of a high level of intratumoral T cells (ITTC) correlated with improved survival compared with a low level of ITTC, with a mean difference in survival of 16.3 months (p=0.006). There was a direct correlation between nSTAT1 expression and ITTC (p<0.001). Patients whose tumours had a high level of ITTC and nSTAT1 survived 20 months longer than those whose tumours had a low level of ITTC and no nSTAT1. A strong correlation was seen between ITTC and MHC class I expression (p=0.0002). A mean survival advantage of 26.1 months was seen in patients whose tumours had strong MHC I expression and high levels of ITTC over those who had weak MHC I and low levels of ITTC (log-rank test=12.023, p=0.034). Both MHC I and ITTC are independent predictors of good survival.


CONCLUSIONS
ITTC, nSTAT1 and strong MHC class I expression on tumours identify patients with improved survival and an intact tumour immune system that may benefit from immunotherapy. Conversely, loss of these markers identifies patients whose tumours have escaped immunosurveillance and are unlikely to benefit from immunotherapy.
Simpson
Jonathan A D
JA
Academic Department of Clinical Oncology, Institute of Immunology, Infections and Immunity, University of Nottingham, City Hospital Campus, Nottingham, UK. lindy.durrant@nottingham.ac.uk
Al-Attar
Ahmad
A
Watson
Nicholas F S
NF
Scholefield
John H
JH
Ilyas
Mohammad
M
Durrant
Lindy G
LG
D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D011379:Prognosis; D017471:Receptors, Interferon / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D000096743:Interferon gamma Receptor
D014408:Biomarkers, Tumor; D015395:Histocompatibility Antigens Class I; D009363:Neoplasm Proteins; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D000096743:Interferon gamma Receptor; C494079:STAT1 protein, human