Manipulating the tumor immune microenvironment to improve cancer immunotherapy: IGF1R, a promising target

Abstract

Cancer immunotherapy has made impressive advances in improving the outcome of patients affected by malignant diseases. Nonetheless, some limitations still need to be tackled to more efficiently and safely treat patients, in particular for those affected by solid tumors. One of the limitations is related to the immunosuppressive tumor microenvironment (TME), which impairs anti-tumor immunity. Efforts to identify targets able to turn the TME into a milieu more auspicious to current immuno-oncotherapy is a real challenge due to the high redundancy of the mechanisms involved. However, the insulin-like growth factor 1 receptor (IGF1R), an attractive drug target for cancer therapy, is emerging as an important immunomodulator and regulator of key immune cell functions. Here, after briefly summarizing the IGF1R signaling pathway in cancer, we review its role in regulating immune cells function and activity, and discuss IGF1R as a promising target to improve anti-cancer immunotherapy.

Keywords: IGF1R; cancer immunity; immuno-oncotherapy; immunomodulation; tumor microenvironment.

Figure 1

The IGF1/IGF1R axis and its downstream signaling pathway. In presence of IGF1, IGF1R activates downstream signaling pathways implicated in cancer cell proliferation and survival as well as in immunomodulation.

Figure 2

Effect of IGF1/IGF1R pathway activation on the immune cell populations of the TME. Activation of the IGF1/IGF1R axis affects differently the indicated immune cell subtypes promoting immunosuppression and cancer progression.

Figure 3

The IGF1/IGF1R axis and the tumor immune microenvironment. Induction of the IGF1R pathway enhances recruitment and activation of immune cells involved in immunosuppression, such as T-regs, M2 macrophages and MDSCs, leading to inhibition of anti-tumor immunity. In contrast, inhibition of the IGF1R pathway or abscence of IGF1 enhance anti-tumor immunity by promoting the recruitment and activation of M1 macrophages and DCs as well as effector cytotoxic CD8⁺ T cells and potentially NK cells.