Author(s): Max Schnurr [*] aff1 , Peter Duewell aff1 , Christian Bauer aff1 , Simon Rothenfusser aff1 , Kirsten Lauber aff2 , Stefan Endres aff1 , Sebastian Kobold aff1
adoptive cellular therapy; immunotherapy; innate immunity; pancreatic cancer; radiotherapy; review; tumor stroma; vaccination
Patients diagnosed with pancreatic cancer face a dismal prognosis due to the aggressive nature of the tumor, late diagnosis and limited treatment benefits offered by chemotherapy or irradiation. Most patients present with locally advanced or metastatic disease and are thus no candidates for surgical resection, currently the only hope for cure. But even those qualifying for surgical resection have a 5-year survival rate of only 20% due to appearance of distant metastases or local recurrence. This stresses the necessity for the development of novel therapeutic approaches [1 ]. Although our understanding of the molecular pathogenesis and deregulated pathways operative in pancreatic cancer has significantly improved over the last decades, especially due to the development of genetically engineered mouse models recapitulating genetic and pathological characteristics found in human tumors, this knowledge has not yet translated into more effective therapies [2 ]. Immunotherapy has gained a tremendous momentum following the reports of unprecedented responses in patients with metastatic melanoma or lung cancer refractory to chemotherapy [3,4 ]. This has prompted the scientific community and pharmaceutical companies to redirect a strategic focus toward immune therapeutics for solid cancers.
For many years, pancreatic cancer has been considered to be poorly immunogenic and thus not amenable to immunotherapy. This view has been challenged by studies revealing that inflammatory responses and immune cells shape biological processes, such as carcinogenesis, tumor growth and metastasis in genetically engineered mouse models [5 ]. Furthermore, several preclinical and clinical studies provide evidence that antitumor immune responses occur spontaneously and can be induced in patients with pancreatic cancer. Tumor-reactive T cells have been isolated from patients and T-cell infiltrations have been identified as a favorable prognostic factor [6 ]. Nevertheless, in most cases T cells fail to control tumor growth and the tumor eventually hijacks immune cells for its own purposes. In fact, a highly immunosuppressive tumor microenvironment can be viewed as a hallmark of pancreatic cancer [7 ]. Several mechanisms mediated by the tumor or associated stromal cells abort T-cell responses via induction of T-cell apoptosis, anergy, dysfunction or ineffective homing.
The challenge for immune-based therapies will be to counteract tumor immune evasion. Strategies under investigation include vaccination with tumor-associated antigens (TAAs), modulation of APC function, adoptive cell transfer (ACT) therapy, restoration of impaired T-cell effector function by checkpoint inhibitors and targeting inhibitory leukocyte populations, such as Tregs, myeloid-derived suppressor cells (MDSCs) or tumor-associated macrophages (TAMs). Recent advances in the field of tumor radiotherapy have demonstrated that irradiation leads to profound immunological changes in the tumor microenvironment that could be exploited for combined radio-immunotherapy. Excellent recent reviews summarize the current knowledge of the role of immune cells in pancreatic cancer development and clinical experiences with immune-based therapies [5,8,9 ]. Our review focuses on current multimodal strategies for tackling tumor-induced immunosuppression that are...