Our laboratory’s overarching goal is to understand how NK cells, in the broader context of the host’s immune system, protect against developing and metastasizing tumor cells, specifically, cancer stem cells, and to understand why this system fails in patients with cancer. Significant heterogeneity of immune potency between individuals with these malignancies has been observed but not explained. We are particularly interested in the questions of how and why the immune system can respond to and control malignant cells in some contexts but not in others. Clarity of the underlying basis for these differences would potentially explain why certain individuals are more susceptible to cancer, lead to better screening strategies, and ultimately provide much needed insight into how the host immune system can be manipulated to control cancer.
Another major focus of our laboratory is to decipher the developmental programs of NK cells. In many patients afflicted with cancer, the NK cells from those individuals do not respond to typical NK cell stimuli. A more complete understanding of NK cell development may ultimately reveal potential ways by which malignancies render NK cells dysfunctional. We are particularly interested in understanding the transcriptional regulation of NK cell development and differentiation from stem and progenitor cells. The goal is to further our understanding of the molecular basis underlying NK cell development and maturation, which will in turn provide much needed insight into disorders associated with NK cell defects. In addition, it will potentially provide an understanding of how the development and differentiation of these special lymphocytes can be modulated for therapeutic purposes.
Modulating ILC Differentiation for Enhanced Tumor Immunity
Natural Killer (NK) cells are critical in the innate immune response against viral infections and cancer. NK cells belong to a family of highly plastic, heterogenous immune cells called Innate Lymphoid Cells (ILCs). ILCs are increasingly studied for their diverse roles in immune defense, organogenesis, and tissue homeostasis. We are interested in studying ILC biology and the ways ILC plasticity can be leveraged to enhance cancer immunotherapies. Specifically, we are investigating the differentiation of an ILC subset that shows heightened reactivity against tumor cells.
Investigating the Role of NSD1 in Immune-Cold Tumors
Immune checkpoint inhibitor therapy shows exciting promise for the treatment of several cancers. However, some tumor-intrinsic factors can render immune checkpoint inhibitors ineffective, and thus, the therapy is only successful in less than 20% of head and neck cancer patients. One such factor is the paucity of infiltration by immune cells. Tumors with low immune cell infiltration are said to have an “immune-cold” phenotype. We are investigating the functional role of mutations in NSD1, a histone methyltransferase, in the development and/or maintenance of the immune-cold phenotype in tumors. With this work, we hope to advance the understanding of the tumor microenvironment, enhance the prognostic tools before treatment, and augment immune checkpoint inhibitor therapy with novel inhibitors.
Identifying Tumor Neoantigens via Mass Spectrometry
Tumor neoantigens can be recognized by tumor infiltrating T cells (TILs) that reside within the tumor tissue. Our lab is interested in identifying targetable tumor neoantigens for T cell therapy of head and neck cancer. In order to assess the specificity of the TILs, we isolate them from resected tumors and expand the TILs in vitro. These TILs can be further probed against putative neoantigens (identified independently via mass spectrometry) and validated using in vitro assays. We hope to identify neoantigens common for many patients with head and neck cancer and characterize T cells that recognize them. This knowledge will serve as a basis for novel immunotherapies.
Elucidating the Contribution of Caspase-8 Mutations in Atypical OSCC
In the most recent Global Burden of Disease study (2017), the global incidence of oral cancer was reported to be 389,760 cases, a rise in incidence from 185,976 cases in 1990. Oral cancer is the most common cancer of the head and neck and has a poor prognosis. The traditional risk factors of oral cancer include smoking, alcohol consumption and HPV infection. In the past few decades, a group of patients with Oral Squamous Cell Carcinoma (OSCC) was observed to lack the traditional risk factors. This atypical group with no known etiology for OSCC has been shown to grow in number over time and are being recognized as a new entity of OSCC. Patients in this group tend to be younger and female, and the tumors behave more aggressively. Our lab is interested in researching the potential involvement of Caspase-8 mutations in the etiology of OSCC in this atypical group.
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- Peder and Kathy Knudsen
- John and Jill Freidenrich
- Simmons Foundation