Immune organ tertiary lymphoid structures (TLSs) as a therapeutic strategy for solid tumors 2247222

Abstract Introduction Tertiary lymphoid structures (TLSs) are linked to better patient outcomes and enhanced immunity in some cancers (e.g. ovarian, lung). TLSs support the reprogramming of immune system to attack the tumor and retain a long-term memory. We employed our previously published TLS-on-chip microfluidic device (TOD) and in vivo murine models to test a novel therapeutic formulation that involves engineering in situ TLSs to combat solid tumors. This formulation aims to generate effector T cells, memory B cells, and tumor-antigen-specific antibodies locally. Methods We integrated different cancer cell lines expressing varying levels of PD-L1/PD-L2 with healthy and cancer patients PBMCs in the TODs to quantify TLS formation, lymphocyte activation, and cancer cell killing. Based on the TOD’s composition, we defined a cellularized extracellular matrix gel to create TLS in vivo. To investigate the in vivo efficacy of this gel, we injected it peritumorally in a lung cancer cell line-derived xenograft (CDX) and a syngeneic model to monitor TLS formation and survival benefit measured by tumor volume reduction. Results TOD studies showed that with “hot” cancer cell lines (high PD-L1/PD-L2), our formulation induced TLS formation leading to a robust cytokine response, B cell activation, anti-tumor CD8+ T cell activity, and cancer cell death. In contrast, “cold” tumor cell lines suppressed TLS formation and the immune response. Peri-tumoral administration of the formulation successfully generated TLSs at the tumor site in a lung cancer CDX model in NSG mice. Intriguingly, they syngeneic lung cancer model showed reduced tumor volume and improved survival in the treated cohort. Conclusion Our findings demonstrate the feasibility of an injectable TLS therapeutic to overcome tumor-mediated immune suppression and generate a potent anti-tumor immune response. This approach has the potential to improve patient survival in challenging solid tumors. Further preclinical development of this promising therapy is ongoing. Funding Source ARPA-H Sprint for Women’s Health award Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)