Cancer dysregulates the immune response to evade cell death and progress throughout the body. As tumors become established, they uptake nutrients and generate a low-oxygen environment, which limits nutrients in the tissue for other cells. Consequently, the surrounding immune cells become dysregulated and cannot function based on the inability to correctly generate adenosine triphosphate (ATP) or energy. The inability for a cell to properly function is referred to as an ‘exhausted’ cell. Specific immune cells that are particularly affected by this include T cells, which are responsible for identifying and targeting the tumor. T cells are optimized to destroy infections throughout the body and are a key readout for effective immune responses. Many different immunotherapies target T cells and are developed to improve their function.
The hypoxic tumor microenvironment (TME) alters T cell function by dysregulating the mitochondria or energy creating organelle. As a result, T cells cannot target tumors and are inert within this cancer-induced pathological state. This is a major barrier to treatment efficacy in patients with cancer. As immunotherapies develop, scientists are learning more about T cell biology and how to better enhance their antitumor function. Since their dysregulation is a result of limited nutrients in the TME, scientists are investigating ways to get the T cell more energy as an avenue for treatment.
A recent article in Nature, by Dr. Ping-Chih Ho and others, demonstrate that T cell exhaustion is the result of accumulation of non-functioning mitochondria. While previous research has shown that T cells become exhausted due to a lack of nutrients, the molecular mechanism behind how this occurs was still unknown. Ho is an Associate Professor of Oncology at Ludwig Cancer Research, University of Lausanne. His work focuses on tumor immunology and how to enhance cancer immunotherapy by targeting metabolic and genetic processes.
Researchers discovered that heme – a iron-bearing molecule in the blood – is released by dysfunctional mitochondria which induces exhaustion. Additionally, by inhibiting this complex process, researchers were able to improve T cell function and enhance immunotherapy.
The team conducted a series of laboratory experiments to understand that normally recycled mitochondria accumulate in tumor-associated T cells. Consequently, the enzymes that normally take part in degrading dysfunctional mitochondria are inhibited, which allow mitochondrial heme-containing proteins to build up. Heme is then released into the nucleus – which contains the cell’s DNA - via PGRMC2 and degrades genetic material causing exhaustion. Researchers found that if this process is not corrected, T cells lose their function. Therefore, by inhibiting PGRMC2 scientists can prevent DNA degradation and improve T cell activity.
Ho and his team have made a foundational discovery that could significantly improve standard-of-care therapy for patients with cancer. This paradigm-shifting work may change the course of immunotherapy. Scientists found that patients with B cell acute lymphoblastic leukemia (B-ALL) have high expression of PGRMC2, which correlates to poor prognosis. However, blocking PGRMC2 in different T cell-based therapies has the potential to significantly improve patient outcomes. Researchers hope to apply this discovery to the clinic and enhance current next-generation cellular therapies.
Article, Nature, Ping-Chih Ho, Ludwig Cancer Research, University of Lausanne.
