This Science Short, written by Mate Z. Nagy, summarizes the following paper: Nagy MZ, Plaza-Rojas LB, Boucher JC, Kostenko E, Austin AL, Tarhini AA, Chen Z, Du D, Ojwang' AME, Davis J, Obermayer A, Rejniak KA, Shaw TI, Guevara-Patino JA. Effector T cells under hypoxia have an altered transcriptome similar to tumor-stressed T cells found in non-responsive melanoma patients. J Immunother Cancer. 2025 Feb 25;13(2):e010153. doi: 10.1136/jitc-2024-010153. PMID: 40010774; PMCID: PMC12086921.
Our immune system is composed of cells equipped to fight foreign pathogens by recognizing and eliminating danger before we become sick, or when we do become sick, they make sure that we don’t stay sick for too long. How does this mighty army of cells do this job, you may ask? Although cells are not consciously thinking and deciding to clear pathogens, they can recognize patterns on foreign invaders as non-self vs self, and act to keep us healthy.
There are first responders, such as neutrophils and macrophages, that recognize patterns on bacteria and fungi as foreign and engulf these invaders [1]. However, at times a disease-causing invader, called a pathogen, evades this first response, and a second line of defense is needed. That’s when a more specialized group of cells called the T and B cells come in and help eliminate the threat. These cells are more specific and create a more robust response that not only eliminates the foreign pathogen but also remembers it so the next time it infects our cells, they can react faster and stronger [2].
Knowing these unique properties of our immune system, scientists have revolutionized how we approach and treat cancers by weaponizing these cells to target tumor cells with immunotherapies.
There are currently multiple cell-based immune therapies for cancer, some in clinical trials and others already in clinic. While the ultimate goal of all of them is to eliminate tumor cells, they all work slightly differently. Tumor Infiltrating Lymphocytes (TIL) therapies work by taking the patient’s T cells out to look for T cells that can target and eliminate the tumor, then enriching this population and injecting these cells back into the patient. The most successful engineered T cells are called Chimeric Antigen Receptor (CAR) T cells. These cells are engineered to make a particular protein for their surface that gives them an advantage in fighting tumor cells, and are then injected into the patient. Think of cell surface proteins like two puzzle pieces fitting together. The one on the T cell will only recognize its counterpart on the tumor cell, leaving other cells alone. Unfortunately, tumor cells have evolved to escape immune recognition by hiding their surface proteins, turning T cells off, or creating such a harsh environment that is not suitable for T cells to survive in.
Hence, there is a need for more robust evaluation and characterization of immune cells for immune therapies.
This is where our paper comes into the story. Melanoma, a type of skin cancer, is notorious for creating a harsh, oxygen-deprived environment, called hypoxia, that is hard for T cells to function and survive in. Knowing this, we set out to understand how far away T cells are from oxygenated areas (using blood vessels as a proxy) in 31 melanoma patients. We found that in the tumor environment of melanoma, T cells accumulate close to blood vessels, suggesting their reliance on oxygen.
Next, to understand the differences between T cells close to blood vessels and those farther from them, we generated and cultured human-derived T cells in a low oxygen environment vs. under normal oxygen levels. We found that the transcriptional profile, or the way a cell uses its genes in response to outside environmental effects, of T cells in a low oxygen environment was similar to that of melanoma patients’ T cells that did not respond to therapy.
To further understand this, we assessed this T cell signature and compared it to publicly available data of T cells from tumors. This dataset includes 16 different tumor types and a comprehensive list of different T cell subsets within tumors, including known populations and unique groups [3]. Our T cells under hypoxia mirrored the group “T cell stress response state”.
In summary, our results suggest three important findings:
· In the tumor environment of melanoma, T cells accumulate close to blood vessels.
· We found a unique transcriptional signature of T cells under low oxygen conditions that correlates with poor patient survival and response to immune therapy.
· Lastly, hypoxic T cells have a similar signature as a population of T cells termed “T cell stress response state” in other tumors.
Overall, our findings show the importance of considering the role of oxygen levels in evaluating T cell therapies. We suggest that screening for hypoxic T cells in patients can help determine the appropriate treatment for individuals. We also hope that a better understanding of T cell fates in cancers can help future T cell engineering and therapies be more potent and successful. Furthermore, we stress the importance of future studies of T cell behavior under different conditions to help better equip T cells to survive in these conditions.
Mate is a rising second year Immunology PhD student. He completed this work at the Moffitt Cancer Center in Tampa, Florida in Dr. Jose Alejandro Guevara’s laboratory during his gap years after receiving his bachelor’s degree in biomedical sciences from the University of Central Florida. His research interest is in T cell immunology and the signaling pathways and mechanisms that govern T cell fates and responses. Mate is an avid outdoors man, wine enthusiast, and huge Philly sports fan. When not in lab, he is either exploring the outdoors, trying new wines, or cheering on the Birds.
References:
1) Silva MT, Correia-Neves M. Neutrophils and macrophages: the main partners of phagocyte cell systems. Front Immunol. 2012 Jul 4;3:174. doi: 10.3389/fimmu.2012.00174. PMID: 22783254; PMCID: PMC3389340.
2) Cano RLE, Lopera HDE. Introduction to T and B lymphocytes. In: Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al., editors. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013 Jul 18. Chapter 5. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459471/.
3) Chu, Y., Dai, E., Li, Y. et al. Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance. Nat Med 29, 1550–1562 (2023). https://doi.org/10.1038/s41591-023-02371-y.