Beeinflussung und Reprogrammierung des Tumormikromilieus in der Tumor-Therapie
Zusammenfassung der Projektergebnisse
CTL infiltration is critical for effectiveness of immune therapies, while infiltration of Treg and MDSCs predicts treatment failures. By investigating two different TLR3 ligands, a selective double-stranded RNA named rintatolimod and the unselective one named Poly-I:C, we achieved for the first time in literature a reprogramming of the TME which achieved selective enhancement of the desired type-1 IFN immunity. Unexpectedly, our current data demonstrate that, while both forms of dsRNA are similarly effective in inducing the intratumoral production of type-1 interferon, only Poly-I:C induced NF-κB-dependent expression of TNFα and COX-2 and the resulting mobilization of Treg/MDSC-attracting chemokines and suppressive factors. This data suggests that selective targeting of type-1 IFN immunity rather than NF-κB can be achieved to enhance antitumor potency of TLR3 based adjuvants and their combinations with other treatments. In addition, these findings may provide an explanation as to why Poly-I:C and its clinical use in cancer treatment is limited by an increased cytotoxicity compared to rintatolimod. Furthermore, we described new mechanisms of exosome-mediated immune suppression. These are the first reports indicating that plasma-derived exosomes of cancer patients do not only reflect tumor activity and disease stage, but also immune competence or suppression of the TME. Additionally, exosomes can directly inhibit functions of immune cells and have the potential to modulate EMT depending on their cargo, which reflects the changes in genetic and molecular components of the parent tumor cell. This work provides new insights into tumor-induced immune suppression, as well as the interaction between immune stimulatory and immune suppressive factors of immune adjuvants. Selective targeting of a certain molecular pathway or elimination of a suppressive one may allow for selective enhancement of a CTL anti-tumor immunity in the human TME. By using exosomes, it is possible to modulate the TME. In addition, exosomes are introduced as another pathway of direct immune cell inhibition. Our future projects will focus on combinatorial treatments of TLR3 signaling and other immune therapies, as well as drug delivery and immune-response monitoring via exosomes in HNSCC patients.
Projektbezogene Publikationen (Auswahl)
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Clinical significance of PD-L1+ exosomes in plasma of Head and Neck Cancer patients. Clin Cancer Res. 2017 Dec 12
Theodoraki MN, Yerneni S, Hoffmann TK, Gooding WE, Whiteside TL
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Suppression of lymphocyte functions by plasma exosomes correlates with disease activity in patients with head and neck cancer. Clin Cancer Res. 2017 Apr 11
Ludwig S, Floros T, Theodoraki MN, Hong CS, Jackson EK, Lang S, Whiteside TL
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Exosomes in HNSCC plasma as surrogate markers of tumor progression and immune competence. Clin Exp Immunol. 2018 Oct;194(1):67-78
Theodoraki MN, Hoffmann TK, Jackson EK, Whiteside TL
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Helicase-driven activation of NFκB-COX2 mediates the immunosuppressive component of dsRNA- driven inflammation in the human tumor microenvironment. Cancer Res. 2018 May 31
Theodoraki MN, Yerneni S, Sarkar SN, Orr B, Muthuswamy R, Voyten J, Modugno F, Jiang W, Grimm M, Basse PH, Bartlett DL, Edwards R, Kalinski P
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Plasma-derived Exosomes Reverse Epithelial-to-Mesenchymal Transition after Photodynamic Therapy of Patients with Head and Neck Cancer. Oncoscience. 2018 Apr 29;5(3-4):75-87
Theodoraki MN, Yerneni SS, Brunner C, Theodorakis J, Hoffmann TK, Whiteside TL
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Separation of plasma-derived exosomes into CD3(+) and CD3(-) fractions allows for association of immune cell and tumor cell markers with disease activity in HNSCC patients. Clin Exp Immunol. 2018 Jun;192(3):271-283
Theodoraki MN, Hoffmann TK, Whiteside TL
