BioAcyl Corp

Cytokine networks are key aspects of tumour immunology, particularly for colorectal cancer (CRC), for which inflammation and antitumour immunity are critical determinants of disease progression.

Interleukin-6 (IL-6) and tumour necrosis factor (TNF) have been studied extensively in CRC and other malignancies and are drivers of signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) pathways, respectively. These cytokines promote malignant progression by enhancing proliferation, invasiveness and resistance to apoptosis.

Studies in both humans and animal models have revealed new players in CRC initiation and progression. Many of these cytokines (IL-17A, IL-22, transforming growth factor-β (TGFβ) and granulocyte–macrophage colony-stimulating factor (GM-CSF)) are necessary for damage repair but are also oncogenic in certain settings.

Several adaptations that allow CRC cells to maximize the benefits that they receive from immune interaction have recently been identified: mutations in TP53 (which encodes p53) enhance IL-6 and TNF signalling; oncogenic KRAS mutations enhance resistance to pro-apoptotic TGFβ signalling; and suppressors of pro-inflammatory signalling such as SOCS3 can be epigenetically silenced.

The pro-tumorigenic or antitumorigenic effects of individual cytokines are context dependent and heavily influenced by synergisms in the complex cytokine milieu. STAT3–NF-κB crosstalk is critical for CRC and can be driven by a number of cytokines with similar biochemical functions.

IL-6 neutralization was unsuccessful in a clinical trial in patients with CRC and is one of the few examples of clinical trials using cytokine-modulatory approaches for CRC. The multitude of pro-tumorigenic cytokines with a role in CRC suggests that the following strategies may enhance therapeutic potential relative to single cytokine blockade: broad-spectrum targeting of receptors shared by several cytokines; combinatorial therapies targeting multiple distinct cytokine pathways; small-molecule inhibitors of cytokine signalling pathways; and/or careful patient stratification based on molecular oncology features to tailor the right immunomodulatory therapies to the right patients.