Interleukin-8 in Colorectal Cancer: A Systematic Review and Meta-Analysis of Its Potential Role as a Prognostic Biomarker

Abstract

Among soluble actors that have emerged as druggable factors, the chemokine interleukin-8 (IL-8) has emerged as a possible determinant of response to immunotherapy and targeted treatment in several cancer types; however, its prognostic/predictive role in colorectal cancer (CRC) remains to be established. We: (i) conducted a systematic review of published literature on IL-8 expression in CRC; (ii) searched public transcriptomics databases; (iii) investigated IL-8 expression, by tumor and infiltrating cells, in a series of CRC samples; and (iv) carried out a meta-analysis of published literature correlating IL-8 expression and CRC prognosis. IL-8 possesses an important role as a mediator of the bidirectional crosstalk between tumor/stromal cells. Transcriptomic analysis indicated that specific IL-8 transcripts were significantly overexpressed in CRC compared to normal colon mucosa. Moreover, in our series we observed a statistically significant correlation between PTEN-loss and IL-8 expression by infiltrating mononuclear and tumor cells. In total, 12 papers met our meta-analysis inclusion criteria, demonstrating that high IL-8 levels significantly correlated with shorter overall survival and progression-free survival. Sensitivity analysis demonstrated a highly significant correlation with outcome for circulating, but not for tissue-detected, IL-8. IL-8 is overexpressed in CRC tissues and differentially produced by tumor or stromal components depending on CRC genetic background. Moreover, circulating IL-8 represents a strong prognostic factor in CRC, suggesting its use in the refining of prognostic CRC assessment and potentially the tailoring of therapeutic strategies in individual CRC patients.

Keywords: IL-8; advanced CRC; anti-angiogenic drugs; chemotherapy; prognosis; tumor–stroma interactions.

Figure 1

Functional consequences of IL-8-mediated crosstalk between tumor and stromal/immune cells within the TME. In the TME, both tumor and stromal/immune cells can release IL-8, which in turn acts as an autocrine or paracrine soluble factor. By mediating TSI, the IL-8 axis affects drug resistance, tumor progression, and clinical outcome in CRC patients. Top panel (in red): IL-8 production by CRC cells during tumor progression is influenced by their genetic background and regulated by the activity of genes such as SPTAN1, LIFR, SMAD4, or BRAF. Once released in the TME, tumor cells-derived IL-8 sustains the acquisition of a local pro-tumoral niche by stimulating neutrophil recruitment and promoting angiogenesis in a paracrine fashion (A). At the same time, IL-8 sustains CSC proliferation and EMT in an autocrine fashion (B), resulting in increased tumor aggressiveness and chemoresistance (C). Bottom panel (in blue): On the other hand, IL-8 can be produced by TME components and modulate TSI, inflammation, and immune response. For example, CAF may stimulate IL-8 release, thereby sustaining CSC proliferation and further promoting angiogenesis locally (D); under stimulation by tumor-secreted micro-vesicles, pro-tumoral N2-neutrophils promote chronic inflammation (E) both locally and systemically, resulting in high levels of IL-8 in the circulation and tissues which, in turn, influences the composition of tumor-infiltrating immune populations and sensitivity/resistance to ICI (F).

Figure 2

Analysis of IL-8 in CRC patients. (A): IL-8 expression in normal and CRC tissues. Boxplots show expression values of the IL-8 gene across 51 CRC samples from the PCAWG resource (“tumor”) and 88 colon samples from the GTEx resource (“normal”) for two transcripts annotated for this gene: ENST00000401931.1 (left panel) and ENST00000307407.3 (right panel). Expression values are given as log2-transformed transcript per million (TPM). (B): Representative CRC cases showing PTEN-loss/IL-8 infiltrate low and IL-8 tumor high images (top panels) and PTEN competent/IL-8 infiltrate high and IL-8 tumor images (bottom panels). Scale bar = 30 μm. Patients carrying PTEN gene inactivating alterations or completely lacking PTEN protein expression (IHC score 0) are referred to as PTEN-loss. (C): Distribution of PTEN competent and PTEN-loss patients according to IL-8 tumor and infiltrate levels. Arrows indicate low or high levels of IL-8.

Figure 3

High IL-8 levels in the circulation and tissues correlates with worse OS. Meta-analysis of the HR for the association of high levels of IL-8 and unadjusted (A), adjusted (B), or unadjusted/adjusted (C) OS data.

Figure 4

High IL-8 levels in the circulation and tissues correlates with worse PFS. Meta-analysis of the HR for the association of high levels of IL-8 and unadjusted/adjusted (A) or adjusted (B) PFS data.

Figure 5

High IL-8 levels in the circulation correlates with worse OS and PFS. Meta-analysis of the HR for the association of the source of IL-8 (plasma or serum) and OS (A) or PFS (B) data.

Figure 6

High IL-8 levels in the circulation, but not tissues, correlates with the clinical outcome of systemic treatment. Meta-analysis of the HR for the association of circulating IL-8 in relation to OS (A,C) or PFS (B) and patients who received anti-angiogenic agents (A,B) or chemotherapy without anti-angiogenic agents (C). Meta-analysis of the HR for the association of IL-8 found in tissues and OS (D) or PFS (E) data.

Figure 7

IL-8 levels do not correlate with the clinical outcome of systemic treatment with/without anti-angiogenic agents. Meta-analysis of the HR for the association of the OS (A) or PFS (B) source and patients who had received chemotherapy with or without anti-angiogenic agents.