Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I)
Refine
Has Fulltext
- yes (1)
Is part of the Bibliography
- yes (1)
Year of publication
- 2018 (1)
Document Type
- Doctoral Thesis (1)
Language
- English (1)
Keywords
- Cancer (1)
- Cancer immunotherapy (1)
- Chemotherapeutic resistance (1)
- Melanom (1)
- Melanoma (1)
- Merkel cell carcinoma (1)
- Merkelzellkarzinom (1)
Institute
Sonstige beteiligte Institutionen
- Harvard Medical School, Boston, USA (1) (remove)
Melanoma and Merkel cell carcinoma (MCC) are highly aggressive cancers of the skin that frequently escape immune recognition and acquire resistance to chemotherapeutic agents, which poses a major obstacle to successful cancer treatment. Recently, a new class of therapeutics targeting the programmed cell death-1 (PD-1) immune checkpoint receptor has shown remarkable efficacy in the treatment of both cancers. Blockade of PD-1 on T cells activates cancer-specific immune responses that can mediate tumor regression. The data presented in this Ph.D. thesis demonstrates that PD-1 is also expressed by subsets of cancer cells in melanoma and MCC. Moreover, this work identifies PD-1 as a novel tumor cell-intrinsic growth receptor, even in the absence of T cell immunity. PD-1 is expressed by tumorigenic cell subsets in melanoma patient samples and established human and murine cell lines that also co-express ABCB5, a marker of immunoregulatory tumor- initiating cells in melanoma. Consistently, melanoma-expressed PD-1 downmodulates T effector cell functions and increases the intratumoral frequency of tolerogenic myeloid- derived suppressor cells. PD-1 inhibition on melanoma cells by RNA interference, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised, and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, including in mice lacking adaptive immunity. Engagement of melanoma- PD-1 by its ligand PD-L1 promotes tumor growth, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuates growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor activates mTOR signaling mediators, including ribosomal protein S6. In a proof-of-concept study, tumoral expression of phospho-S6 in pretreatment tumor biopsies correlated with clinical responses to anti-PD-1 therapy in melanoma patients. In MCC, PD-1 is similarly co-expressed by ABCB5+ cancer cell subsets in clinical tumor specimens and established human cell lines. ABCB5 renders MCC cells resistant to the standard-of-care chemotherapeutic agents, carboplatin and etoposide. Antibody-mediated ABCB5 blockade reverses chemotherapy resistance and inhibits tumor xenograft growth by enhancing chemotherapy-induced tumor cell killing. Furthermore, engagement of MCC-expressed PD-1 by its ligands, PD-L1 and PD-L2, promotes proliferation and activates MCC-intrinsic mTOR signaling. Consistently, antibody- mediated PD-1 blockade inhibits MCC tumor xenograft growth and phosphorylation of mTOR effectors in immunocompromised mice. In summary, these findings identify cancer cell-intrinsic functions of the PD-1 pathway in tumorigenesis and suggest that blocking melanoma- and MCC-expressed PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy. Additionally, these results establish ABCB5 as a previously unrecognized chemoresistance mechanism in MCC.