This year’s American Association for Cancer Research (AACR) annual meeting took place on 1–5 April in Washington, DC, USA. The program committee Chair was Kornelia Polyak, MD, PhD, from the Dana-Farber Cancer Institute, Boston, Massachusetts.
On Sunday 2nd April, during the “RAOS02 - Immunotherapy of Lymphoid Malignancies” session, Dean W. Felsher, MD, PhD, from the Stanford University School of Medicine, gave a talk titled: “The Myc Oncogene is a Master Regulator of the Immune Response.”
Dr Felsher began the talk by highlighting that oncogene dependency can be a cancer’s “Achilles heel”; knocking out the oncogene can cause cancer cells to differentiate (displaying a normal phenotype) or to undergo apoptosis.
MYC is a transcription factor with multiple functions and plays a role in a wide range of cellular pathways; because of this, MYC contributes to multiple cancer traits:
Dr Felsher went on to explain that in a tet inducible mouse model, enabling MYC to be turned on and off, it was found that MYC induced lymphomagenesis can be reversed. Moreover, switching MYC off in lymphoma resulted in cell cycle arrest, differentiation, and apoptosis:
The talk then discussed the role of MYC in cellular senescence: suppression of MYC results in cellular senescence in a variety of tumor types, including lymphoma.
Following this, Dr Felsher outlined findings published by Wu et al. in the Proceedings of the National Academy of Sciences of the United States of America in 2007: programs of cellular senescence stay latently functional, even in established tumors, and these programs can be activated again, providing a crucial mechanism of oncogene addiction associated with inactivation of MYC.
An overview was then given of how inactivation of MYC results in regression of tumors:
The focus of the talk then turned to whether MYC regulates the immune system and if this influences stemness versus senescence?
An active immune system is crucial for continual regression of tumors, for stimulating oncogene addiction, and CD4+ T-cells specifically are needed to induce cellular senescence after inactivation of MYC (Rakhra et al. Cancer Cell, 2010).
- MYC regulates expression of two immune checkpoint proteins on the surface of tumor cells: CD47 (innate immune regulator) and PD-L1 (adaptive immune checkpoint)
- MYC binds directly to Cd47 and Pd-l1 genes promoters
- Silencing MYC in mouse tumors and human tumor cells decreased levels of CD47 and PD-L1 mRNA and protein, and enhanced the antitumor immune response
However, inactivating MYC in tumors with enforced expression of CD47 or PD-L1 resulted in repression of the immune response and continual tumor growth
Dr Felsher then presented an overview slide of how oncogenes and the immune response interact:
The talk was concluded by stating that cancers, including Lymphomas such as Burkitt Lymphoma, Mantle Cell Lymphoma, and Double Hit Lymphoma, may potentially be cured by inactivating the MYC oncogene. MYC inactivation reinstates the immune response against cancer. Dr Felsher also suggested that nanoscale proteomics (NIA) provide a potential strategy of identifying oncogene activation in patients, informing therapeutic choice.