Alexis Combes, PhD
The immune system functions as a coordinated set of diverse cell types and signaling activities that act as a primary driver and reflection of the state of human health. The Combes lab is a highly collaborative team who uses a system immunology approach to discover and dissect recurring patterns of the immune system in health and disease.
The past decade has seen a revolution in cancer treatment due to a shift from traditional chemotherapy and radiation-based therapies toward the use of antibody-based immunotherapies that modulate the immune response against tumors. However, the clinical responses to immunotherapy in patients has been highly variable and still mainly restricted to cancer. Therefore, a deeper understanding of the diversity of the immune microenvironment across diseases is critical to expand the reach of immunotherapy in tumors as well as other diseases.
Our laboratory uses immune monitoring and high-dimensional single cell technologies both on tumor of animal model and clinical samples to show the existence of archetypal organization of immune systems in tissue—collections of cell types that move together as modules. As opposed to focusing on the state of a single cell type, we considered the prevalence of a collection of cells with linked states. The prototypical collections of these cells that define the system and its functional goals can then be considered an archetype of the immune response. Using this approach in solid tumors, we recently identified conserved dominant tumor immune archetypes characterized by distinct immune networks and tumor transcriptomic programs for each archetype with unique relationships among immune cells and chemokine networks. The tumors archetypes provide an immune classification that is distinct from individual tumor types and it improved classification of patients such that we could identify those with effective antitumor T-cell responses. We are now using this framework to understand and dissect the linked cell states sustaining those archetypes across tumors to guide the next round of immunotherapies.
The concept of immune archetype is not limited to cancer. Therefore, in the lab we are also working toward building an atlas of the different immune archetype across tissues and biological systems to explore the parallels in immune states across conditions, and how we may better stratify patients using measurements of the immune system to improve diagnoses and treatment. This is enabled by the Disease-to-biology CoLab, a collaboration-based research lab where we provide our expertise to the broader UCSF research community to profile the immune system in various sets of tissues and organism. This teamwork will dissect the different immune archetypes in different contexts and will guide the development of relevant precision therapies that are aimed at adjusting the relative strengths of these archetypes depending on the disease.