A major function of our immune system is to recognize and eliminate cancer cells. Insights into interactions between cancer and immune cells has led to the development of transformative therapeutics like immune checkpoint inhibition (ICI) and chimeric antigen receptor T cells (CAR-Ts). Further advances in our understanding of the tumor immune environment are likely to not only lead to better therapeutics, but also improved methods for early detection as immune responses can be magnified even in the presence of small tumors. The Lastwika Lab focuses on lung cancer early detection, imaging, and treatment by translating an aspect of tumor immunity called autoantibodies (AAbs). AAbs are produced by B lymphocytes in response to modified ‘self’-antigens expressed in diseases like autoimmunity and cancer (Figure 1A).
Most current approaches for AAb detection utilize capture reagents that do not reflect disease-relevant epitopes (i.e., fixed/linearized epitopes, recombinant proteins produced in other species) or have labor intensive deciphering of the capture antigen on the back end. To overcome this limitation, we’ve collaborated extensively with Paul Lampe’s lab who developed a high-density antibody microarray to isolate AAb-antigen complexes directly from patients (Figure 1B).
This platform uniquely enables us to simultaneously detect AAbs bound to their native tumor-derived epitopes ex vivo and identify the cognate antigen. Our lab has shown autoantibodies bind neoantigens created by post-translational modifications (PTM) like citrullination, isoaspartylation and cancer-specific glycosylation. Identifying these immunogenic epitopes on the tumor cell surface is key- we exploit this anti-tumor immune response to direct us to highly specific targets missed by other genomic approaches. We use antigen-specific PTM-tetramers to select for B cells directly from cancer patient peripheral blood mononuclear cells (PBMCs) (Figure 1C).
PTM-tetramer captured B cells are then single cell sorted, the VH and VL are sequenced and then cloned into human IgG expression vectors. By taking advantage of the immune system’s intrinsic ability to differentiate between diseased and normal tissue, we are translating AAbs into highly specific early detection biomarkers and diagnostic immunoPET imaging reagents, as well as therapeutics like antibody drug conjugates or chimeric antigen receptors (Figure 1D).
