We are all familiar with cellular metabolism and how the production of ATP (cell energy) is critical for cell development, proliferation, and survival. Understanding the impact of immuno-metabolism and how this area can enhance the ever-evolving immuno-oncology research is a new and exciting field. Since the cells of the immune system are a fundamental component of the tumor microenvironment (TME), cancer immunotherapy continues to be a powerful therapeutic approach to use the immune system to produce an anti-tumor response. Increasing evidence suggests that down regulation of cellular metabolism plays a pivotal role in inhibiting the ability of the immune system to inhibit tumor growth. In the TME, the immune cells are forced to operate with a metabolic disadvantage since they are subjected to a lack of energy resources. This is mainly due to the competition between the immune cells and the tumor cells for limited nutrients.1
The Balancing Act of Reprogramming Resting Naïve T Cells Into Activated Effector T Cells
In this blog we focus on the impact that immuno-metabolism has on the T cell populations. The T cell immune response is comprised of several steps; T cell activation, expansion, and the acquisition of effector functions. All are energy demanding processes that are accompanied by, and dependent upon, marked changes in nutrient uptake and cellular metabolism. Each subset of T cells has a distinct metabolic profile that regulates its function. The transition from resting naïve T cell into activated effector T cell requires substantial metabolic reprogramming; which requires the T cells to balance the metabolic demands of energy maintenance, cell survival, and persistence in each phase. This balancing act requires the utilization of diverse metabolic cycles.2 For example, memory CD8+ T cells take advantage of the abundance of ATP produced by the TCA and fatty acid oxidation cycles, while the effector T cells rely on glycolysis and fatty acid synthesis to support and promote proliferation.3 However, immuno-metabolism is also affected by several signaling pathways and transcription factors. A few key targets that are widely researched include mTOR, Myc, and AMP-activated protein kinase.2 These pathways are not only responsible for cell growth and proliferation, but also, nutrient levels, energy status, and T cell activity. This becomes even more critical as the immune cells are in direct competition with the aggressive growth of cancer cells.
Targeting Exhausted T Cells
In a tumor, the T cells can become exhausted and lose the capacity to properly respond to stimulation. This lack of responsiveness may be due to the cell’s inability to optimally utilize appropriate metabolic pathways. It has been reported that exhausted T cells down regulate several genes involved in energy metabolism. Also, CTLA-4 and PD-1 expressed on exhausted T cells may also be restraining the T cells from correctly remodeling metabolism thus reducing their function. Targeting exhausted T cells by trying to increase glycolysis may be a way to reactivate these cells,1 but this could also increase the growth potential of tumor cells.
Targeting Glucose Metabolism, the mTor Pathway, and the Direct Metabolic Pathway to Restore Tumor Immunity and Develop Anti-Cancer Therapy
In cancer, T cell activation and proliferation are impaired by the metabolic disruption caused by the tumor cells. Therefore, targeting tumor metabolism has become an attractive strategy to restore anti-tumor immunity and develop novel anti-cancer therapies. However, as with any cancer treatment, there are many obstacles that need to be considered. For example, targeting glucose metabolism to treat cancer has been shown to reduce T cell formation and increase T regulatory cell formation. Targeting the mTOR pathway is important for inhibiting cell proliferation but also suppresses immuno-metabolism. The metabolic pathways can also be targeted directly. There are several molecules designed to inhibit glycolysis, fatty acid synthesis/oxidation and the TCA cycle. Balancing between cancer cell suppression and immune cell development and proliferation is very challenging given that these two processes oppose each other. As immune metabolism research grows, scientists will have to consider the impact these functions have on each other.
Written by: Erin Trachet | Sr. Scientific Advisor, Oncology / Sr. Manager, Proposal Development
1Soumaya Kouidhi, Farhat Ben Ayed and Amel Benammar Elgaaied “Targeting Tumor Metabolism: A New Challenge to Improve Immunotherapy” Front. Immunol., 23 February 2018.
2David O’Sullivan, Erika L. Pearce “Targeting T Cell Metabolism for Therapy” Trends in Immunology; Volume 36, Issue 2, p71–80, February 2015.
3O’Neill LA1, Kishton RJ2, Rathmell J2. “A Guide to Immunometabolism for Immunologists” Nat Rev Immunol. 2016 Sep;16(9):553-65. doi: 10.1038/nri.2016.70. Epub 2016 Jul 11.