Transcriptional determinants of cancer immunotherapy response and resistance

Abstract

The host immune response is a potent defense mechanism against cancer development and progression. To survive, cancer cells must develop mechanisms to evade the immune response. Based on this knowledge, a series of new therapies collectively referred to as immunotherapies have been developed and translated to the clinic for treating cancer patients. Although some cancer subtypes have shown strong clinical responses, including curative outcomes in some patients, immunotherapies have not worked as desired for some subtypes and forms of cancers. We provide an overview of the transcriptional mechanisms that drive the response and resistance to immunotherapies. We also discuss possible interventions to enhance the outcomes of immunotherapies by targeting dysregulated transcriptional networks in cancer cells.

Keywords: epigenetics; gene regulation; immunotherapy; transcription.

Figure 1.. Approaches for cancer immunotherapies.

Based on the understanding of immune evasion mechanisms by cancer cells, a series of approaches to enhance immune system-mediated eradication of cancer cells have been implemented. Key immunotherapeutic approaches are depicted.

Figure 2, Key Figure.. Transcriptional mechanisms that drive response and resistance to cancer immunotherapies.

Schematic depicting the role of transcription profile changes, DNA methylation changes, and changes in transcription factor and chromatin regulators on immune cell function and the immunotherapeutic response.

Figure 3.. Clinical translation of transcription targeting therapies in combination with cancer immunotherapies.

New studies have revealed the immune stimulatory effects of DNA methylation and chromatin regulatory proteins resulting in the use of the DNMT inhibitor decitabine and the HDAC inhibitors entinostat and vorinostat in combination with ICB therapies and CAR-T cells.