• Enhancing tumor antigen presentation with complement targeted liposomes

      Francian, Alexandra; Kullberg, Max; Kuhn, Thomas; Burkhead, Jason; Knall, Cindy (2021-08)
      Tumor-mediated immune evasion and suppression can be prohibitive to successful cancer treatment and recovery. A defining trait of cancer progression is when tumor cells develop the ability to evade detection by the immune system. Advanced tumors can suppress the presentation of antigens to effector immune cells by secreting regulatory cytokines and by downregulating the expression of major histocompatibility complex I (MHC I) receptors on the surface of tumor cells. Effective anti-tumor immunity requires the processing and persistent presentation of tumor antigens to effector cells. The cells responsible for this are antigen presenting cells (APCs), which initiate the immune response against cancer by engulfing and presenting tumor antigens to effector immune cells. APCs present tumor antigens, which provide specific targets for helper T cells and cytotoxic T lymphocytes, allowing the immune system to distinguish cancer cells from noncancerous cells. There are many different types of tumor antigens, and the increased effort to sequence reactive epitopes and establish a database makes tumor antigen immunotherapy a promising avenue for treatments and vaccines. Immunotherapies have been developed to restore the immune response against tumors without the toxic side effects of chemotherapeutic drugs. This research describes a promising cancer immunotherapy utilizing a liposome nanoparticle that binds to endogenous complement C3 proteins in serum and is internalized by APCs through the complement C3 receptor, resulting in direct delivery of encapsulated compounds. APCs were shown to internalize C3-bound liposomes containing ovalbumin (OVA), a model antigen, resulting in a significant increase in activated T cells that recognize OVA, reduced tumor growth in all mice (n=5), and complete elimination of both treated and distal tumors in two out of five mice (40%). Blood from treated mice had lower percentages of immunosuppressive cells, higher percentages of B cells, and increased anti-OVA IgG1. Collectively, treatment with OVA C3-liposomes is able to induce the activation of both cell-mediated and humoral immune responses. C3-liposomes encapsulating a melanoma tumor antigen, TRP-2, were able to reduce and eliminate established tumors in a melanoma tumor model in 6 out 7 mice (86%), with the addition of checkpoint blockade, anti-CTLA-4, improving the results (tumor reduction in all mice; n=3). C3-liposomes were also able to induce expression of costimulatory molecules and the production of proinflammatory cytokines and factors in targeted APCs. These results indicate that C3-liposome delivery of tumor antigens to APCs initiates a potent and systemic antitumor immune response.