Combined Exosome Release Inhibitory & Fibroblast Phenotype Reversal Nanomedicines Normalize CAFs & Potentiate Cancer Immunotherapy

Principal Investigator: Shiladitya Sengupta

Authors: Ahmed Elzoghby 1*, Mostafa Tawfik 1, May Freag  1, Arpita Kulkarni 1, Hae Lin Jang  1 and Shiladitya Sengupta 1,2,3* 1 Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. 2 Dana Farber Cancer Institute, Boston, MA, USA. 3 Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA. *e-mail: ;
Lay Abstract

Some of the cells in the tumor microenvironment like fibroblasts help protect cancer cells from attack by the host immune system. There is a mutual crosstalk between cancer cells and fibroblasts through release of tumoral extracellular vesicles and internalization into fibroblasts to help tumorigenesis and immunosuppression. My work is to develop a therapeutic strategy that help the immune system to fight cancer cells by blocking that cancer-fibroblast crosstalk. We show that some drugs incorporated into nanoparticles targeted to cancer cells can inhibit the transfer of extracellular vesicles from cancer cells to fibroblasts thus inhibiting their activation and blocking that crosstalk. In parallel, we demonstrated the efficacy of another drug combination nanomedicine targeted to cancer associated fibroblasts to reverse the activated CAFs phenotype to a normalized one that has anti-tumoral effect. Co-administration of both nanomedicines significantly improves cancer cell killing effect and hence boosts the antitumor efficacy of conventional cancer immunotherapy in mice model of lung cancer.

Scientific Abstract

Normalization of cancer associated fibroblasts (CAFs) and reversal of its immunosuppressive phenotype is a major therapeutic goal. Cancer cells secrete exosomes and other factors to reprogram fibroblasts and induce their differentiation into pro-tumorigenic fibroblasts (CAFs). Also, cancer cells maintain the activated fibroblast phenotype via activating certain signaling pathways, e.g. TGFβ1, FGFR, or Wnt/β-catenin pathways in the fibroblasts. Here, our goal was to maintain a normalized quiescent phenotype of fibroblasts to enhance the efficacy of immune checkpoint inhibitors. We show that a tumor-targeted shikonin/GW4869 combination nanomedicine synergistically inhibits the biogenesis and release of exosomes from A549 lung cancer cells which remarkably prevents differentiation of MRC5 lung fibroblasts into CAFs. In parallel, we demonstrated the efficacy of another TAS120/ICG001 FGFR-Wnt/β-catenin inhibitor combination nanomedicine displaying GPR77 and CD10 targeting antibodies to reverse the acquired activated CAFs phenotype to a quiescent one. Co-administration of both nanomedicines significantly improves the infiltration of cytotoxic T cells and enhances the antitumor efficacy of αPD-L1 antibody in syngeneic mice model of lung cancer. Simultaneously blocking the tumoral exosome-mediated activation of fibroblasts and FGFR-Wnt/β-catenin signaling axes may constitute a promising immunotherapeutic approach.

Clinical Implications
The goal of my research is to develop nanodisc-based immunomodulator that inhibits tumoral exosome release and increase tumor antigenicity. If successful it can offer a new paradigm in immunotherapy of ‘cold’ cancers by boosting both innate and adaptive immune response.

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