Abstract
BackgroundCancer-related immune antigens in the tumor microenvironment could represent an obstacle to agents targeting EGFR “cetuximab” or VEGF “bevacizumab” in metastatic colorectal cancer (mCRC) patients.MethodsInfiltrating immune cells into tumor tissues, cancer-related expression of immune antigens (CD3, CD8, CD68, CD73, MPO, CD15/FUT4) from 102 mCRC patients receiving first-line Cetuximab or Bevacizumab plus chemotherapy were assessed by immunohistochemistry and validated in an independent tissue microarrays of 140 patients. Genome-wide expression profiles from 436 patients and 60 colon cancer cell lines were investigated using bioinformatics analysis. In vitro kinase assays of target genes activated by chemokines or growth factors were performed.ResultsHere, we report that cancer-related CD15/FUT4 is overexpressed in most of mCRCs patients (43 %) and associates with lower intratumoral CD3+ and CD8+ T cells, higher systemic inflammation (NLR at diagnosis >5) and poorer outcomes, in terms of response and progression-free survival than those CD15/FUT4-low or negative ones (adjusted hazard ratio (HR) = 2.92; 95 % CI = 1.86–4.41; P < 0.001). Overexpression of CD15/FUT4 is induced through RAF-MEK-ERK kinase cascade, suppressed by MEK inhibitors and exhibits a close connection with constitutive oncogenic signalling pathways that respond to ERBB3 or FGFR4 activation (P < 0.001). CD15/FUT4-high expressing colon cancer cells with primary resistance to cetuximab or bevacizumab are significantly more sensitive to MEK inhibitors than CD15/FUT4-low counterparts.ConclusionCancer-related CD15/FUT4 overexpression participates in cetuximab or bevacizumab mechanisms of resistance in mCRC patients. CD15/FUT4 as a potential target of the antitumor immune response requires further evaluation in clinical studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0225-7) contains supplementary material, which is available to authorized users.
Highlights
In the last decade, metastatic colorectal carcinoma treatment has radically improved, thanks to the introduction, into clinical practice of novel agents targeting EGFR and VEGF pathways [1,2,3,4,5].Cancer is driven by activating mutations and aberrant signal transduction node, most of which (RAS, PTEN, EGFR) play a significant role in the prediction of resistance to epidermal growth factor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer (mCRC) treatment, whereas, equivalent reliable predictors of bevacizumab are currently lacking [1, 2, 6, 7]
Cancer is driven by activating mutations and aberrant signal transduction node, most of which (RAS, PTEN, EGFR) play a significant role in the prediction of resistance to epidermal growth factor receptor (EGFR) monoclonal antibodies in mCRC treatment, whereas, equivalent reliable predictors of bevacizumab are currently lacking [1, 2, 6, 7]
We have recently proposed that malignant cells can “express” ectopic immune epitopes, which are typical of immune cells (i.e., CD73, CD68) and that these may serve as tumor antigens to evade immune surveillance facilitating homotypic interactions in distant organs during metastatic process [20]
Summary
Metastatic colorectal carcinoma (mCRC) treatment has radically improved, thanks to the introduction, into clinical practice of novel agents targeting EGFR and VEGF pathways [1,2,3,4,5].Cancer is driven by activating mutations and aberrant signal transduction node, most of which (RAS, PTEN, EGFR) play a significant role in the prediction of resistance to epidermal growth factor receptor (EGFR) monoclonal antibodies in mCRC treatment, whereas, equivalent reliable predictors of bevacizumab are currently lacking [1, 2, 6, 7]. Increasing studies underscore the involvement of immune cells, through an emerging hallmark of cancer, evoked as evasion of immune surveillance [9,10,11]. In keeping with this concept, a higher infiltration of memory cytotoxic Th1 T-lymphocytes and tumor-associated neutrophils (TANs) correlate with a longer survival, evidencing the critical effect of host immune response on tumor evolution and clinical outcome [11,12,13,14,15,16]. Cancer-related immune antigens in the tumor microenvironment could represent an obstacle to agents targeting EGFR “cetuximab” or VEGF “bevacizumab” in metastatic colorectal cancer (mCRC) patients
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