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 CD103+CD8+ 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. Cancer Res; 78(2); 475-88. ©2017 AACR.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death and tumor resection is still the only potentially curative treatment [1]
In a transgenic mouse model of locally induced, resectable PDAC, we found that neoadjuvant PD1 blockade/gemcitabine suppressed local recurrence and improved survival in both natural killier (NK) cell and T-cell–dependent manner
In line with the survival results, the individual evaluation of metastasis patterns revealed that additional adjuvant treatment with aPD-1 did not affect the proportions of local recurrence and distant metastasis compared with adjuvant gemcitabine alone
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death and tumor resection is still the only potentially curative treatment [1]. Because PDAC patients are prone to develop systemic metastasis early in the course of the disease, the risk of tumor recurrence remains extraordinarily high with a 5-year survival rate of 10% after surgery alone and up to 25% with adjuvant chemotherapy, preferably gemcitabine [2]. A phase II study showed an improved 5-year survival rate to 36% when patients received gemcitabine and radiotherapy prior to pancreaticoduodenectomy [3]. To achieve a sustained therapeutic benefit after tumor surgery for the vast majority of PDAC patients, further treatment options have to be considered to effectively prevent local tumor recurrence and outgrowth of distant metastases that are undetectable at the time of resection
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