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  P72 - Tumor Biology and Systems Biology - Basic and Translational Science - Tumor Microenvironment (ID 211)

  • Event: WCLC 2020
  • Type: Posters
  • Track: Tumor Biology and Systems Biology - Basic and Translational Science
  • Presentations: 1
  • Moderators:
  • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall

  • 35909

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    P72.07 - Modulation of the Tumor Microenvironment by Targeting ERb/HER Oncogenic Network in Lung Cancer Produces Synergy when Followed by Immunotherapy (ID 3291)

    00:00 - 00:00  |  Presenting Author(s): Abdulaziz Abdullah Almotlak
    • Abstract
    • Slides

    Introduction
    

    The tumor microenvironment (TME) is a key contributor to lung cancer progression. Current treatment modalities that target TME to boost the antitumor immune response have shown promising results in lung cancer. However, low response rate and acquired resistance are frequently common with these therapeutic agents, suggesting combinatorial cocktail approach is highly needed to improve outcomes. We previously showed that inhibiting the ER.

    Methods
    

    Here, we evaluated the effects of F+D on cultured murine bone marrow-derived macrophages (BMDMs) and CD8+ T cells, and tested the efficacy of F+D in vivo using a novel syngeneic lung adenocarcinoma model, FVBW17 (KRAS-G12D⁺/TP53⁺).

    Results
    

    We found that while F+D synergistically suppressed proliferation of FVBW17 cancer cells, the combination had an unwanted immunosuppressive effect by reducing CD8+ T cell activity, promoting an M2-phenotype in BMDMs, and inducing PD1. Effects were largely attributed to the action of D through downregulation of Src family kinases and spleen tyrosine kinase (Syk) in immune cells. In a xenograft model, F+D induced an inflamed TME characterized by increased infiltration of CD11b+/F4/80+ myeloid cells and CD8+ T cells, but the TME showed signs of immunosuppression, which both could predict better response to immunotherapy. Indeed, concomitant administration of anti-PD1 antibody with F+D significantly reduced immunosuppression at the tumor site and in the spleen. Only the triple therapy that significantly reduced both PD1+/CD8+ T cells and CD206+/F480+ myeloid cells (M2 cells) at the tumor site. Concomitant triple therapy also significantly reduced tumor volumes. Administering anti-PD1 after F+D in a sequential approach (a week of F+D then another week with anti-PD1) was synergistic, with a two-fold greater effect compared to concomitant therapy and fold-folds greater than placebo (combination ratio of 1.35). Anti-PD1 alone was ineffective in this model. The synergistic effect of sequential therapy was recapitulated when FVBW17 cells were established in the lungs via IV injection. The average number of lung tumors was 10 in the sequential triple therapy compared to 15 in the concomitant triple therapy (p= 0.002), 20 in F+D group (p= 0.0001), and 38 in the placebo group (p= 0.0005). The triple therapy groups showed increased lung infiltration of CD8+ T cells and an overall reduced expression of the immunosuppressive marker VEGF.

    Conclusion
    

    Targeting multiple aspects of lung tumorigenesis is feasible and the triple therapy of F+D and anti-PD1 given sequentially showed improved efficacy and tolerability, and has potential to treat aggressive lung cancer unresponsive to current therapies.

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