Immune-based therapies have revolutionized the way cancer patients are treated; however, most patients do not benefit from these current treatments. Dr. Overacre-Delgoffe seeks to understand why certain patients do not respond and, along with others in the field, has found that the bacteria (microbes) that reside within the gut can impact this response across cancer types. Dr. Overacre-Delgoffe's research group has previously shown that microbes control the type of immune response formed during colorectal cancer, and that the relationship between microbes and a person’s immune system is critical to effectively fight cancer. Dr. Overacre-Delgoffe plans to tackle a new question: How do microbes residing in the gut impact cancer growth and response to immune-based therapies in cancer types outside of the gut, for example melanoma and pancreatic cancers? Results from this project will lead to a better understanding of therapy resistance mechanisms as well as identify new treatments for patients who do not benefit from current treatments.

Dr. Ramanan studies the interplay between commensal microbes and immune cells in the intestine, and how these interactions influence the progression of inflammation and colorectal cancer. Immune fitness of an individual is thought to be the result of ongoing interactions between genetics and microbial exposure. A fundamental and often overlooked aspect of immunity, however, is the effect of maternal and environmental factors in early life. She uncovered a novel mode of non-genetic multigenerational transfer of immune traits (entero-mammary axis). She will utilize this tool to understand how maternal factors can modulate immune responses to infections, inflammation, and colorectal carcinoma.

Endogenous retroviruses are viral elements of the human genome derived from retroviral infections of distant ancestors. Recent findings support the idea that these elements can cause immune system activation and inflammation. However, the crosstalk between endogenous retroviruses and the gut microbes that control immunity within the gut-and how abnormalities in this dialogue lead to inflammatory disorders-is not well understood. Further, although endogenous retroviruses have been proposed as potential targets for immunotherapy, we lack a mechanistic understanding of their interactions with the gut microbiota and how these interactions influence cancer development. Dr. Rivera Cifuentes [Lorraine W. Egan Fellow] aims to uncover how multi-kingdom interactions in the gut control intestinal health and colorectal cancer development. This work may have important clinical implications for the treatment of gut inflammatory disorders and gastrointestinal cancers. Dr. Rivera Cifuentes received her PhD from the University of Paris, Paris and her BSc from The Pontifical Catholic University of Chile, Santiago.

Normal tissues naturally weed out harmful cells to prevent cancer. But when cancer develops, this defense system breaks down, allowing the cancer to attack healthy cells for its own growth. The Shaffer lab is set to explore this process, called cell competition, in esophageal cancer. By employing precise tracking and advanced spatial analysis, Dr. Shaffer aims to reveal how cell competition contributes to cancer development and how it might be harnessed to prevent it. The goal of her research is to pioneer early intervention therapies to halt cancer in its tracks.

Neutrophils are important anti-microbial cells within the innate immune system. Recently, it has been shown that neutrophils can perform diverse functions, taking on both pro-inflammatory and pro-healing roles in response to tissue injury or insult. Dr. Siwicki's [Dale F. and Betty Ann Frey Fellow] goal is to understand how different neutrophil subtypes or states function to balance inflammatory versus regenerative processes, ultimately influencing tissue health and cancer. This work has the potential to uncover the basis of neutrophils' pro-tumor versus anti-tumor functions and could open the door to therapeutic targeting of specific neutrophil behaviors in order to improve clinical outcomes in cancer. Dr. Siwicki received her PhD from Harvard Medical School, Boston and ScB from Brown University, Providence.

Groundbreaking advances in immunotherapy have revolutionized the treatment of cancer. In particular, new antibody drugs that block immunosuppressive pathways have achieved remarkable success in reawakening the immune system to clear tumor cells, leading to lasting cures in patients whose cancers do not respond to any other therapies. Unfortunately, the majority of patients (>70%) do not respond to immunotherapy treatment. It is difficult to predict which patients will benefit, creating an urgent demand for novel immunotherapy drugs that act through alternative mechanisms. Dr. Spangler is working to develop a class of antibody therapeutics that target cancer-promoting pathways in a different way than all current immunotherapies, with the goal of drastically expanding the percentage of cancer patients who benefit from them.

One of the tools cancer cells employ to evade immune system detection is an increased DNA mutation rate, with some cancers mutating 100-1000 times faster than healthy tissue. Classic studies of the effects of mutations predict that most genetic changes are deleterious, yet high mutation rates appear to help cancer cells adapt and invade. Dr. Triandafillou [National Mah Jongg League Fellow] will address this paradox by using a single-cell model of cancer to measure the effects of mutations with much greater accuracy and resolution than is possible in live cancer cells. This information will help us understand how cancer cells balance deleterious mutations with the ability to adapt, and how the effects of mutations interact. She will also perform laboratory evolution experiments to track the adaptive process in different environmental conditions, mimicking the process by which cancer cells are able to colonize new micro-environments within tumors and throughout the body. This work will provide a clearer picture of how cancer cells use new mutations to proliferate. Dr. Triandafillou received her PhD from the University of Chicago and her BS from Temple University.

Dr. Vardhana [Gordon Family Clinical Investigator] is exploring the hypothesis that gastric cancers create an inhospitable environment for immune T-cells by limiting the availability of essential nutrients needed by T-cells to produce the cytotoxic proteins that, when released, kill cancer cells. There is evidence that T-cells lose the ability to produce cytotoxic proteins within gastric tumors, while gastric tumors take up and sequester amino acids—the building blocks of all proteins, including cytotoxic proteins—such that they cannot be accessed by T-cells within tumors. Understanding and reversing this metabolic sequestration within gastric tumors may be a novel strategy to enhance T-cell immunity within gastric tumors.

Extrachromosomal DNA (ecDNA), or DNA not attached to a chromosome, has been found in nearly half of human cancer types, especially in aggressive cancers such as glioblastoma, neuroblastoma, leukemia, lung, and ovarian cancer. Despite being a potent cancer driver, the mechanisms underlying ecDNA regulation remain largely unexplored. Combining both advanced imaging and cutting-edge sequencing technologies, Dr. Yan [Connie and Bob Lurie Fellow] is investigating how ecDNA is spatially organized in cells and genetically inherited over generations. She hopes to reveal new mechanisms of DNA regulation and inheritance other than the canonical chromosome and help develop new ways to treat patients with ecDNA-driven cancers. Dr. Yan received her PhD from the University of California, San Francisco, and her BS from Peking University.

Emerging evidence underscores the profound impact of the gut microbiome, a collection of microorganisms within our digestive system, on cancer. These microorganisms collectively generate various metabolites that can significantly influence cancer progression and treatment outcomes. Dr. Zeng is employing synthetic communities and mouse cancer models to delve into the intricate connections between cancer and the microbiome. His synthetic communities, comprised of over 100 strains, allow for precise manipulation of the microbiome to elucidate the role of specific microbial metabolites in cancer. Additionally, Dr. Zeng is studying community-scale metabolism and using genetically edited strains to design synthetic communities with desired metabolic profiles. These approaches will gain valuable insights into microbiome-cancer interactions and establish a broadly applicable strategy to harness the therapeutic potential of gut microbiome. Dr. Zeng received his PhD from Princeton University, Princeton and his BS from Tsinghua University, Beijing.