One of the hallmarks of cancer is evading an immune response that should recognize emerging cancers as foreign and eliminate them. Immunotherapies are recent major breakthroughs in cancer treatment that reactivate the immune system to recognize and kill tumor cells. These novel treatments include immune checkpoint blockade where therapeutic antibodies remove a powerful break on the immune system to restore tumor killing, and cellular therapies where the patients’ own immune cells are engineered with superior tumor killing ability and then returned to the patient. Unfortunately, these new transformative treatments are only effective in a small subset of patients. If we could find the means to make immunotherapies more effective more broadly, it would transform cancer treatment and the lives of cancer patients.
One way to improve the anti-cancer immune response is by altering metabolism. Metabolic function and metabolite production can inhibit or promote activity of the immune system, but how they do so is poorly understood. It is the goal of the Ludwig Princeton Branch to understand how metabolism in tumor cells, the tumor microenvironment, and immune cells enables immune evasion. With that knowledge, we can identify the means to control metabolism through use of metabolic pathway inhibitors, metabolite supplementation, and dietary manipulation to restore the immune response to cancer and make immunotherapies more effective.
Related Publications
Xu X, Chen Z, Bartman CR, Xing X, Olszewski K, Rabinowitz JD. One-carbon unit supplementation fuels purine synthesis in tumor-infiltrating T cells and augments checkpoint blockade. Cell Chem Biol. 2024 May 16;31(5):932-943.e8. doi: 10.1016/j.chembiol.2024.04.007. PMID: 38759619.
Nucleotides perform important metabolic functions, carrying energy and feeding nucleic acid synthesis. Here, we use isotope tracing-mass spectrometry to quantitate contributions to purine nucleotides from salvage versus de novo synthesis. We further explore the impact of augmenting a key precursor for purine synthesis, one-carbon (1C) units. We show that tumors and tumor-infiltrating T cells (relative to splenic or lymph node T cells) synthesize purines de novo. Shortage of 1C units for T cell purine synthesis is accordingly a potential bottleneck for anti-tumor immunity. Supplementing 1C units by infusing formate drives formate assimilation into purines in tumor-infiltrating T cells. Orally administered methanol functions as a formate pro-drug, with deuteration enabling kinetic control of formate production. Safe doses of methanol raise formate levels and augment anti-PD-1 checkpoint blockade in MC38 tumors, tripling durable regressions. Thus, 1C deficiency can gate antitumor immunity and this metabolic checkpoint can be overcome with pharmacological 1C supplementation.
Sawant A, Shi F, Lopes EC, Hu Z, Abdelfattah S, Baul J, Powers J, Hinrichs CS, Rabinowitz JD, Chan CS, Lattime EC, Ganesan S, White E. Immune Checkpoint Blockade Delays Cancer and Extends Survival in Murine DNA Polymerase Mutator Syndromes. bioRxiv [Preprint]. 2024 Jun 12:2024.06.10.597960. doi: 10.1101/2024.06.10.597960. PMID: 38915517; PMCID: PMC11195045.
Mutations in polymerases Pold1 and Pole exonuclease domains in humans are associated with increased cancer incidence, elevated tumor mutation burden (TMB) and response to immune checkpoint blockade (ICB). Although ICB is approved for treatment of several cancers, not all tumors with elevated TMB respond. Here we generated Pold1 and Pole proofreading mutator mice and show that ICB treatment of mice with high TMB tumors did not improve survival as only a subset of tumors responded. Similarly, introducing the mutator alleles into mice with Kras/p53 lung cancer did not improve survival, however, passaging mutator tumor cells in vitro without immune editing caused rejection in immune-competent hosts, demonstrating the efficiency by which cells with antigenic mutations are eliminated. Finally, ICB treatment of mutator mice earlier, before observable tumors delayed cancer onset, improved survival, and selected for tumors without aneuploidy, suggesting the use of ICB in individuals at high risk for cancer prevention.
Zhong H, Lu W, Tang Y, Wiel C, Wei Y, Cao J, Riedlinger G, Papagiannakopoulos T, Guo JY, Bergo MO, Kang Y, Ganesan S, Sabaawy HE, Pine SR.Oncogene. 2023 Jun;42(27):2183-2194. doi: 10.1038/s41388-023-02715-5. Epub 2023 May 31.PMID: 37258742
The SOX9 transcription factor ensures proper tissue development and homeostasis and has been implicated in promoting tumor progression. However, the role of SOX9 as a driver of lung adenocarcinoma (LUAD), or any cancer, remains unclear. Using CRISPR/Cas9 and Cre-LoxP gene knockout approaches in the KrasG12D-driven mouse LUAD model, we found that loss of Sox9 significantly reduces lung tumor development, burden and progression, contributing to significantly longer overall survival. SOX9 consistently drove organoid growth in vitro, but SOX9-promoted tumor growth was significantly attenuated in immunocompromised mice compared to syngeneic mice.