Immunomodulation by MYB is associated with tumor relapse in patients with early stage colorectal cancer

Abstract

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.

High c-Myb Expression Associates with Good Prognosis in Colorectal Carcinoma

“…As we and others previously reported that high c-Myb expression in CRC cell lines enhanced their chemorezistance 24-26, the „metastasis hypothesis“ seems to be more relevant. It should be noted, however, that high c-Myb protein level was associated with poor prognosis in gallbladder adenocarcinoma 27, 28 and esophageal squamous cell carcinoma 29 and two previous studies by Ramsay group reported that high c-Myb associates with poor prognosis in CRC patients 30, 31. While Millen et al found an association between c-Myb level and relapse-free survival in a small cohort of preselected CRC patients (only T2 patients, cases with deficient mismatch repair excluded) 30, Biroccio et al reported a relation between c-Myb, DFS and OS in a 91 CRC patients (70 colon, 21 rectum) without any preselection 31.…”

“…It should be noted, however, that high c-Myb protein level was associated with poor prognosis in gallbladder adenocarcinoma 27, 28 and esophageal squamous cell carcinoma 29 and two previous studies by Ramsay group reported that high c-Myb associates with poor prognosis in CRC patients 30, 31. While Millen et al found an association between c-Myb level and relapse-free survival in a small cohort of preselected CRC patients (only T2 patients, cases with deficient mismatch repair excluded) 30, Biroccio et al reported a relation between c-Myb, DFS and OS in a 91 CRC patients (70 colon, 21 rectum) without any preselection 31. Although there are some differences in design of our study and that of Biroccio group (inclusion of patients with tumor localized in rectum by Biroccio et al, different proportions of patients in group T1/T2 vs T3/T4, the length of follow-up, immunohistochemistry protocol etc.)…”

“…Future effort is required to uncover yet unidentified mechanisms of c-Myb action in CRC tumor progression. It has been recently suggested that c-Myb-modulated interaction between cancer cells and immune system within tumor- and metastasis-specific microenvironment may be crucial in this context 16, 18, 30. As therapies targeting c-Myb have been already tested in preclinical studies 32, 33 and undergo further development, the understanding of c-Myb function is of great importance before they enter clinical trials.…”

Identification of key genes involved in tumor immune cell infiltration and cetuximab resistance in colorectal cancer

“…Paradoxically, patients with CRC and high MYB expression exhibit low incidence of distant metastases [38] and favorable clinical prognosis tumor immune infiltrating cells and a clinical history of longer relapse-free survival were related to high expression of MYB. An immunomodulatory effect conferred by MYB was also observed in CD8 + TILs in the murine CRC model [40]. CDX-2 encodes a regulator of intestinespecific genes involved in cell growth and differentiation.…”

Identification of potential novel drug resistance mechanisms by genomic and transcriptomic profiling of colon cancer cells with p53 deletion

“…Overexpression of the MYB transcription factor (+ 28.8-fold expression in knockout cells) has been associated with poor prognosis and was frequently observed in colorectal cancer (CRC) (Cross et al 2015 ). Another study pointed out that MYB expression in tumor cells due to its tumorigenic role modulated the host immune response, which has the potential to influence the use of immunotherapy in CRC patients (Millen et al 2016 ). MYC (+ 5.1-fold) is another transcription factor with a critical role in tumorigenesis.…”