Perioperative, spatiotemporally coordinated activation of T and NK cells prevents recurrence of pancreatic cancer

Jennifer Brooks, Bettina Fleischmann-Mundt, Norman Woller, Julia Niemann, Silvia Ribback, Kristin Peters, Ihsan Ekin Demir, Nina Armbrecht, Guralp O. Ceyhan, Michael P. Manns, Thomas C. Wirth, Stefan Kubicka, Gunter Bernhardt, Mark J. Smyth, Diego F. Calvisi, Engin Gurlevik, Florian Kuhnel

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and disseminating cancer resistant to therapy, including checkpoint immunotherapies, and early tumor resection and (neo)adjuvant chemotherapy fails to improve a poor prognosis. In a transgenic mouse model of resectable PDAC, we investigated the coordinated activation of T and natural killier (NK) cells in addition to gemcitabine chemotherapy to prevent tumor recurrence. Only neoadjuvant, but not adjuvant treatment with a PD-1 antagonist effectively supported chemotherapy and suppressed local tumor recurrence and improved survival involving both NK and T cells. Local T-cell activation was confirmed by increased tumor infiltration with CD103þCD8þ T cells and neoantigen-specific CD8 T lymphocytes against the marker neoepitope LAMA4-G1254V. To achieve effective prevention of distant metastases in a complementary approach, we blocked the NK-cell checkpoint CD96, an inhibitory NK-cell receptor that binds CD155, which was abundantly expressed in primary PDAC and metastases of human patients. In gemcitabine-treated mice, neoadjuvant PD-1 blockade followed by adjuvant inhibition of CD96 significantly prevented relapse of PDAC, allowing for long-term survival. In summary, our results show in an aggressively growing transgenic mouse model of PDAC that the coordinated activation of both innate and adaptive immunity can effectively reduce the risk of tumor recurrence after surgery, facilitating long-term remission of this lethal disease. Significance: Coordinated neoadjuvant and adjuvant immunotherapies reduce the risk of disease relapse after resection of murine PDAC, suggesting this concept for future clinical trials.

Original languageEnglish
Pages (from-to)475-488
Number of pages14
JournalCancer Research
Volume78
Issue number2
DOIs
StatePublished - 15 Jan 2018
Externally publishedYes

Fingerprint

Dive into the research topics of 'Perioperative, spatiotemporally coordinated activation of T and NK cells prevents recurrence of pancreatic cancer'. Together they form a unique fingerprint.

Cite this