The development of immunological memory is necessary for protection against infection in the long term. In acute infection, after T cells expand and clear the pathogen, they will form memory T cells whose role is to surveil the body for the same pathogen. Our lab has been at the forefront of identifying the genetic and transcriptional regulators of immunological memory. Currently, we are focused on the spatial and metabolic cues that dictate memory formation, while also applying the latest genetic and protein engineering approaches towards the development of better memory.
A hallmark of cancer is metabolic reprogramming by tumor cells to adapt to a rapidly changing metabolic environment created by their own overconsumption. It is unclear how immune cells can adapt in the same environment without sacrificing its own effector function. In this way, tumors can suppress an immune response through metabolic regulation. We are focused on understanding how key characteristics of tumor metabolism (e.g. hypoxia, fatty acid synthesis, eicosanoids) influence immune cell function. By identifying the key metabolic regulators of immune function in tumors, we hope to reveal novel targets to turn immunologically “cold” tumors into “hot” ones that are susceptible to immunotherapy.
T cells become dysfunctional or ‘exhausted’ in chronic viral infections and cancer. Exhausted cells are marked by reduced cytokine production and profound epigenetic change that limits their ability to be rejuvenated with immune checkpoint blockade. We understand exhaustion to be a result of chronic antigen exposure, and epigenetic change is seen early and mediated by the transcription factor TOX. What is still unknown are the particular dynamics of exhaustion, especially how T cells resolve chronic signals, and the metabolic regulation of exhaustion. These studies will help us to better understand how T cells become exhausted in chronic infections.
Microglia are the resident macrophages of the central nervous system. While their major function is to maintain tissue homeostasis, their dysfunction is linked to the progression of disease, including Alzheimer’s and glioma. We are working to understand the role that these cells play in disease, and how that is dictated by their metabolic state, so as to find novel approaches to promote microglia functionality.
The emergence of immunotherapy, including checkpoint blockade, has made previously hard-to-treat cancers suddenly treatable by rejuvenating antitumor immunity by T cells. However, the majority of patients either do not respond to treatment or acquire resistance. Lacking in the field is an understanding what dictates response to immunotherapy, and what drives some patients to acquire resistance. We hope to not only find ways to enhance the efficacy of immunotherapy, but also identify those patients who could benefit the most from immunotherapy.
11/19 – Many congratulations to those in Kaechland who have won awards! Congratulations to Kay for winning a Damon Runyan fellowship, and Karthik and Shixin for winning fellowships from CRI. Victor was even more successful winning a SITC fellowship, and the award for best oral presentation at LJIC. Also congratulations to Ali and Zoe for winning best poster presentations at LJIC.
03/19 – A great month in Kaechland! Kay Chung was awarded both a Salk Women & Science award and the AACR Anna D. Barker Basic Cancer Research Fellowship. Also winning awards are Karthik, who won a postdoctoral fellowship from the NOMIS Center, and Victor, who was awarded a T32 training fellowship. Congratulations to our awesome postdocs!