Protein homeostasis in immunotherapy of cancer

Immune-based treatment approaches with immune checkpoint inhibitors have shown notable anticancer activity. Unfortunately, resistance to this type of treatment occurs in many patients, emphasizing the need for a better understanding of the heterogeneous mechanisms of resistance. As immunotherapies become more prominent in the treatment of cancer, there is an immense need for understanding the mechanisms of immune checkpoint inhibitor resistance and for the development of new therapeutic strategies to induce long-term responses.

Tumours often develop various mechanisms to evade immune destruction. Accordingly, the resistance mechanisms are heterogeneous, including cancer cell intrinsic mechanisms as well as environment-dependent and T-cell-dependent mechanisms. One mechanism that tumour cells often utilize to escape immune cell-mediated killing is defective antigen presentation. Intracellular antigens presented on the surface of cancer cells are often cleaved by the proteasome, which is a large multisubunit protease shaped like a narrow barrel with three different protease subunits in the middle of the barrel. The proteasome is a key player in cellular protein homeostasis, affecting antigen presentation.

Our team has long-term expertise in studying drug resistance in myeloma and solid tumours and in manipulating protein homeostasis in cancer cells in vitro and in vivo. By combining CRISPR/Cas9 genome-wide screens with various omics, single-cell analysis and cell biology approaches, we study protein homeostasis in cancer cells with the aim of identifying the intrinsic mechanisms driving the resistance of cancer cells to immunotherapy.