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Triple-negative breast cancer (TNBC) is characterized by high cell proliferation, abundant heterogeneity, frequent incidence of lung and brain metastases, repeated disease recurrence, and the worst prognosis among all breast cancer subtypes. Extensive evidence from translational studies indicates immunosuppressive cell infiltration into the tumor microenvironment (TME) promotes tumor immune escape and inhibits the efficient antitumor immune response. Previously, we have shown that a large proportion of tumor-infiltrating lymphocytes in claudin-low subtype of TNBC are CD4+FoxP3+ Tregs. Infiltration of Treg in TME is associated with suppressing effector T cell responses, accelerated tumor growth, and poor clinical outcomes. Herein, to convert immunosuppressive TME of TNBC to immune-inflamed immunophenotype we used polymeric micelles nanoparticles for co-delivering immunomodulatory small molecule drugs. We used a novel Full Spectral Flow Cytometry approach for immunophenotyping tumors. We identified significant infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs) in the orthotopic T11 TNBC tumor. The small molecule resiquimod, an imidazoquinoline Toll-like receptor (TLR) 7/8 agonist, and idelalisib, an inhibitor of phosphatidylinositol 3-kinase (PI3K) p110δ were incorporated in poly(2-oxazoline) block copolymer polymeric micelle NPs. Drug exposure to tumor cells was increased by the small-size nanoparticles associated with the preferential accumulation of NPs in tumors. The resiquimod and idelalisib were used to differentiate MDSC and selectively decrease the number and function of Tregs in TME, respectively. Following targeted radiation therapy in combination with iv administration of nanoformulation to animals bearing orthotopic T11 TNBC tumors, we observed significant suppression of tumor growth and enhanced overall survival compared to targeted radiotherapy alone. Radiation therapy in combination with both nanoformulated resiquimod and idelalisib induced optimal tumor control, increasing median survival with over 50% complete response rate, while all mice in the nanoformulation groups or radiation alone group succumbed to tumor growth. Enhanced adaptive T cell immunity against TNBCs and effective therapeutic improvement in immunocompetent mice following radiotherapy were only observed with simultaneous depletion of Tregs and MDSC. These data suggest radiotherapy in combination with nanoparticle co-delivery of immunomodulators inhibiting MDSCs and Treg, has promising potential for future clinical trials and translation for the treatment of TNBC patients. Citation Format: Mostafa Yazdimamaghani, Oleg Kolupaev, Chaemin Lim, Duhyeong Hwang, Alexander Kabanov, Jonathan Serody. Enhanced anti-breast tumor cancer activity using nano-formulated TLR 7/8 agonist and PI3K inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1810. |
