Ivana William

reservoir has a critical function in sustaining antitumor T cells during tumor development and in protecting them from the terminal differentiation that occurs in the TME.

STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade-resistant model, where 100% of mice were cured. Ex vivo flow cytometry profiling during the therapeutic window demonstrated increases in myeloid tumor trafficking and activation, alongside enhancement of CD8+ T cell and NK effector responses. Treatment with 8803 reprogrammed microglia to express costimulatory CD80/CD86 and iNOS, while decreasing immunosuppressive CD206 and arginase. In humanized mice, where tumor cell STING is epigenetically silenced, 8803 therapeutic activity was maintained, further attesting to myeloid dependency and reprogramming. Although the combination with a STAT3 inhibitor did not further enhance STING agonist activity, the addition of anti-PD-1 antibodies to 8803 treatment enhanced survival in an immune checkpoint blockade-responsive glioma model. In summary, 8803 as a monotherapy demonstrates marked in vivo therapeutic activity, meriting consideration for clinical translation.

Kras-driven lung adenocarcinoma (LUAD) is the most common lung cancer. A significant fraction of patients with Kras-driven LUAD respond to immunotherapy, but mechanistic studies of immune responses against LUAD have been limited because of a lack of immunotherapy-responsive models. We report the development of the immunogenic KP × NINJA (inversion inducible joined neoantigen) (KP-NINJA) LUAD model. This model allows temporal uncoupling of antigen and tumor induction, which allows one to wait until after infection-induced inflammation has subsided to induce neoantigen expression by tumors. Neoantigen expression is restricted to EPCAM+ cells in the lung and expression of neoantigen was more consistent between tumors than when neoantigens were encoded on lentiviruses. Moreover, tumors were infiltrated by tumor-specific CD8 T cells. Finally, LUAD cell lines derived from KP-NINJA mice were immunogenic and responded to immune checkpoint therapy (anti-PD1 and anti-CTLA4), providing means for future studies into the immunobiology of therapeutic responses in LUAD.