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Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance

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A Correction to this article was published on 01 September 2021

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Abstract

To date, the use of immune checkpoint inhibitors has proven largely ineffective in patients with advanced pancreatic ductal adenocarcinoma. A combination of low tumor antigenicity, deficits in immune activation along with an exclusive and suppressive tumor microenvironment result in resistance to host defensives. However, a deepening understanding of these immune escape and suppressive mechanisms has led to the discovery of novel molecular targets and treatment strategies that may hold the key to a long-awaited therapeutic breakthrough. In this review, we describe the tumor-intrinsic and microenvironmental barriers to modern immunotherapy, examine novel immune-based and targeted modalities, summarize relevant pre-clinical findings and human experience, and, finally, discuss novel synergistic approaches to overcome immune-resistance in pancreatic cancer. Beyond checkpoint inhibition, immune agonists and anti-tumor vaccines represent promising strategies to stimulate host response via activation and expansion of anti-tumor immune effectors. Off-the-shelf natural killer cell therapies may offer an effective method for bypassing downregulated tumor antigen presentation. In parallel with this, sophisticated targeting of crosstalk between tumor and tumor-associated immune cells may lead to enhanced immune infiltration and survival of anti-tumor lymphocytes. A future multimodal treatment strategy involving immune priming/activation, tumor microenvironment reprogramming, and immune checkpoint blockade may help transform pancreatic cancer into an immunogenic tumor.

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  1. Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Thatcher Heumann & Nilofer Azad

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Dr. Heumann has no conflict of interests. Dr. Azad receives research funding from BMS, Merck, Incyte, Syndax, Intensity, Bayer, EMD Serono. She receives financial compensation as a consultant for AstraZeneca and Merck/EMD Serono.

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Heumann, T., Azad, N. Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance. Cancer Metastasis Rev 40, 837–862 (2021). https://doi.org/10.1007/s10555-021-09981-3

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