Small molecule immunomodulation: the tumor microenvironment and overcoming immune escape

Abstract

Immunotherapy has led to a paradigm shift in the treatment of many advanced malignancies. Despite the success in treatment of tumors like non-small cell lung cancer (NSCLC) and melanoma, checkpoint inhibition-based immunotherapy has limitations. Many tumors, such as pancreatic cancer, are less responsive to checkpoint inhibitors, where patients tend to have a limited duration of benefit and where clinical responses are more robust in patients who are positive for predictive biomarkers. One of the critical factors that influence the efficacy of immunotherapy is the tumor microenvironment (TME), which contains a heterogeneous composition of immunosuppressive cells. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) alter the immune landscape of the TME and serve as facilitators of tumor proliferation, metastatic growth and immunotherapy resistance. Small molecule inhibitors that target these components of the TME have been developed. This special issue review focuses on two promising classes of immunomodulatory small molecule inhibitors: colony stimulating factor-1 receptor (CSF-1R) and focal adhesion kinase (FAK). Small molecule inhibitors of CSF-1R reprogram the TME and TAMs, and lead to enhanced T-cell-mediated tumor eradication. FAK small molecule inhibitors decrease the infiltration MDSCs, TAMs and regulatory T-cells. Additionally, FAK inhibitors are implicated as modulators of stromal density and cancer stem cells, leading to a TME more conducive to an anti-tumor immune response. Immunomodulatory small molecule inhibitors present a unique opportunity to attenuate immune escape of tumors and potentiate the effectiveness of immunotherapy and traditional cytotoxic therapy.

Keywords: Colony stimulating factor; Focal adhesion kinase; Immune escape; Immunomodulation; Immunotherapy; Small molecules; Tumor microenvironment.

Fig. 1

Major cellular constituents and mediators of the TME, including cancer cells, immune cells (T-cells, B-cells, dendritic cells, MDSCs, TAMs), cytokines, CAFs and the extracellular matrix

Fig. 2

Signaling pathways for CSF-1 and FAK. CSF-1R predominantly modulates differentiation, proliferation and survival via PI3K or the RAF/MEK/ERK pathway. For the regulation of cell adhesion and migration, the binding of CSF-1 to CSF-1R leads to phosphorylation of FAK, which in turn activates numerous signaling pathways that lead to actin polymerization/cytoskeleton remodeling, adhesion dynamics and migration (via ERK, N-WASP/CDC42, VCAM and Selectin). However, like CSF-1/CSF-1R, FAK is also involved in cell survival via the PI3/AKT pathway. Interaction of ECM protein (e.g. fibronectin) with integrins can also activate FAK, which leads to ligand-independent phosphorylation of CSF-1R, and thus cell migration (inset on left lower portion of Fig. 1)