Immunomodulation by MYB is associated with tumor relapse in patients with early stage colorectal cancer.
The presence of tumor immune infiltrating cells (TILs), particularly CD8(+) T-cells, is a robust predictor of outcome in patients with colorectal cancer (CRC). We revisited TIL abundance specifically in patients with microsatellite stable (MSS) CRC without evidence of lymph node or metastatic spread. Examination of the density of CD8(+) T-cells in primary tumors in the context of other pro-oncogenic markers was performed to investigate potential regulators of TILs. Two independent cohorts of patients with MSS T2-4N0M0 CRC, enriched for cases with atypical relapse, were investigated. We quantified CD8(+) and CD45RO(+) -TILs, inflammatory markers, NFkBp65, pStat3, Cyclo-oxygenase-2 (COX2) and GRP78 as well as transcription factors (TF), β-catenin and MYB. High CD8(+) TILs correlated with a better relapse-free survival in both cohorts (p = 0.002) with MYB and its target gene, GRP78 being higher in the relapse group (p = 0.001); no difference in pSTAT3 and p65 was observed. A mouse CRC (CT26) model was employed to evaluate the effect of MYB on GRP78 expression as well as T-cell infiltration. MYB over-expressing in CT26 cells increased GRP78 expression and the analysis of tumor-draining lymph nodes adjacent to tumors showed reduced T-cell activation. Furthermore, MYB over-expression reduced the efficacy of anti-PD-1 to modulate CT26 tumor growth. This high MYB and GRP78 show a reciprocal relationship with CD8(+) TILs which may be useful refining the prediction of patient outcome. These data reveal a new immunomodulatory function for MYB suggesting a basis for further development of anti-GRP78 and/or anti-MYB therapies.
Peter MacCallum Cancer Center and The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne ,Victoria, Australia; St Vincent's Hospital, Fitzroy, Victoria, Australia.
Rosemary
R
Millen
Peter MacCallum Cancer Center and The Sir Peter MacCallum Department of Oncology, University of Melbourne , Melbourne ,Victoria, Australia.
Jordane
J
Malaterre
Peter MacCallum Cancer Center and The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne ,Victoria, Australia; The Department of Pathology, University of Melbourne, Melbourne Victoria, Australia.
Ryan S
RS
Cross
Peter MacCallum Cancer Center and The Sir Peter MacCallum Department of Oncology, University of Melbourne , Melbourne ,Victoria, Australia.
Sandra
S
Carpinteri
Peter MacCallum Cancer Center and The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne ,Victoria, Australia; Royal Melbourne Hospital and Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
Jayesh
J
Desai
Royal Melbourne Hospital and Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute , Parkville, Victoria, Australia.
Ben
B
Tran
Peter MacCallum Cancer Center and The Sir Peter MacCallum Department of Oncology, University of Melbourne , Melbourne ,Victoria, Australia.
Phillip
P
Darcy
Royal Melbourne Hospital and Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute , Parkville, Victoria, Australia.
Peter
P
Gibbs
Royal Melbourne Hospital and Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute , Parkville, Victoria, Australia.
Oliver
O
Sieber
St John of God Subiaco Hospital, Subiaco, Western Australia, Australia; The School of Surgery, The University of Western Australia, Nedlands, Western Australia, Australia.
Nikolajs
N
Zeps
The Department of Pathology, University of Melbourne , Melbourne Victoria, Australia.
Paul
P
Waring
Peter MacCallum Cancer Center and The Sir Peter MacCallum Department of Oncology, University of Melbourne , Melbourne ,Victoria, Australia.
Stephen
S
Fox
Peter MacCallum Cancer Center and The Sir Peter MacCallum Department of Oncology, University of Melbourne , Melbourne ,Victoria, Australia.
Lloyd
L
Pereira
Peter MacCallum Cancer Center and The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne ,Victoria, Australia; The Department of Pathology, University of Melbourne, Melbourne Victoria, Australia.
Robert G
RG
Ramsay
CD8+ve T Cells; GRP78; MYB; early stage colorectal cancer