Constitutionally EGFR-independent colorectal cancers have accelerated growth rates through IL10-mediated anergy
Colorectal cancers can arise and progress independent of epidermal growth factor receptor, partially through IL10-dependent anergy. This subset of colorectal cancers can be inhibited using IL10 neutralizing antibodies, providing a new therapeutic approach to increase efficacy of EGFR inhibitors.
The epidermal growth factor receptor (EGFR) is a key factor in epithelial malignancies by promoting tumor growth and metastasis. Not surprisingly, EGFR is a prime target for therapeutic intervention. However, only 15% of CRC patients respond to EGFR inhibition (1). Although previous studies have revealed several mechanisms for resistance (2), the lack of dependency on EGFR for colorectal tumor progression has not been fully tested until now.
We used two different mouse models and 3D culture of colon tumor organoids to definitively stablish the existence of a subset of colon polyps that arise independent of EGFR, and in the absence of EGFR, polyps are more likely to arise and have an accelerated growth rate irrespective of Kras status.
Comparative transcriptomics revealed a unique gene expression signature related to EGFR-independent polyps. We found that based on directionality of the gene expression levels, human colorectal cancers correspond to EGFR-dependent and independent polyps found in mice. Furthermore, similar to the accelerated growth of EGFR-independent polyps in the mouse model, human colorectal cancers predicted to be EGFR-independent had lower survival rates.
We further showed that IL10, potentially through SRC signaling, regulates immune activity by suppressing inflammatory responses in EGFR-independent polyps and favors differentiation of monocytes toward M2-like macrophages, which accumulate in the tumor microenvironment (3). Increased levels of IL10 in the TME induced expression of anergy-associated genes, allowing tumor cells to escape the immune response. Consistent with transcriptomic analysis and the computational prediction of EGFR-independent signature in humans, increased levels of IL10 in serum have been associated with lower survival in colorectal cancer patients (4). We show that IL10 neutralizing antibodies inhibit growth of EGFR independent tumors in vitro and in vivo.
Our results have important implications for EGFR-targeted therapies. Our findings suggest that EGFR inhibitors not be effective against a subset of colorectal cancers that constitutionally arises independent of EGFR through hyperactivation of IL10RA signaling. Categorizing colorectal cancers as dependent or independent of EGFR will improve outcomes of EGFR targeted therapeutics. Furthermore, combination therapies with IL10 neutralizing antibodies and EGFR inhibitors should be considered for EGFR-independent cancers.
- Yang YH, et al. Comparison of cetuximab to bevacizumab as the first-line bio-chemotherapy for patients with metastatic colorectal cancer: superior progression-free survival is restricted to patients with measurable tumors and objective tumor response--a retrospective study. J Cancer Res Clin Oncol 140, 1927-1936 (2014).
- Martins M, Mansinho A, Cruz-Duarte R, Martins SL, Costa L. Anti-EGFR Therapy to Treat Metastatic Colorectal Cancer: Not for All. Adv Exp Med Biol 1110, 113-131 (2018).
- Solinas G, Germano G, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 86, 1065-1073 (2009).
- Zhao S, Wu D, Wu P, Wang Z, Huang J. Serum IL-10 Predicts Worse Outcome in Cancer Patients: A Meta-Analysis. PLoS One 10, e0139598 (2015).