Cancer Letters

Cancer Letters

Volume 407, 28 October 2017, Pages 57-65
Cancer Letters

Mini-review
PD-1/PD-L1 and immunotherapy for pancreatic cancer

https://doi.org/10.1016/j.canlet.2017.08.006Get rights and content

Highlights

  • Underlying mechanisms of single anti-PD-1/PD-L1 immunotherapy failure are proposed.

  • Immunoediting process refers to immune profiles, TME types and immune resistance.

  • Combination therapy modulating the immunoediting process can overcome the failure.

Abstract

Therapy that targets programmed death 1 or programmed death 1 ligand 1 (PD-1/PD-L1), which are known as immune checkpoints, has been recently rapidly developing as oncotherapy for various carcinomas. However, this therapy has a poor effect on the treatment of pancreatic cancer with PD-1/PD-L1 blockade monotherapy. In this review, the development and limitations of anti-PD-1/PD-L1 monotherapy in pancreatic cancer are discussed. We then consider the underlying mechanism of anti-PD-1/PD-L1 monotherapy failure, combination strategies overcoming resistance to anti-PD-1/PD-L1 immunotherapy and the prospect of targeting PD-1/PD-L1 for the immunotherapy of pancreatic cancer.

Introduction

Pancreatic cancer is a highly lethal human cancer, with a 7% 5-year overall survival rate [1], [2]. This malignancy is the fourth and sixth leading cause of cancer-related deaths in the USA and China, respectively [1], [3]. Because early diagnosis is difficult, the therapeutic efficacy is unsatisfactory, and the prognosis is poor, this lethal disease has always been an active research topic in oncological surgery. The primary therapeutic strategies include surgery and chemotherapy. However, only 20% of patients are resectable, and chemoresistance is a very common phenomenon. A growing understanding of the pathogenesis of pancreatic cancer has led to immunotherapy on the basis of stimulating and mobilizing the human immune system, and enhancing the anti-tumour capacity of the tumour microenvironment has become a research focus in the treatment of pancreatic cancer. Immunotherapy of pancreatic cancer is classified into four categories according to the different immune response mechanisms activated by neoplasms: specific active immunotherapy, specific passive immunotherapy, nonspecific adoptive immunotherapy and nonspecific immune regulation [4], [5], [6]. Therapy targeting programmed death 1 or programmed death 1 ligand 1 (PD-1/PD-L1), known immune checkpoints, has been recently rapidly developing for the oncotherapy of various carcinomas. However, the treatment of pancreatic cancer with a single PD-1/PD-L1 blockade has a poor effect. In this review, we will first primarily discuss the development and limitations of targeting PD-1/PD-L1 in the immunotherapy of pancreatic cancer. The underlying mechanism of therapy failure and the prospect of targeting PD-1/PD-L1 in the immunotherapy of pancreatic cancer will then be discussed in the latter section.

Section snippets

PD-1/PD-L1

PD-1, an immune checkpoint expressed by activated T cells that was supposed to be involved in the classical type of programmed cell death, was initially cloned in 1992 [7]. PD-L1 was subsequently identified and characterized in 2000, and it has since been regarded as an immune checkpoint [8]. Tumour-associated PD-L1 was confirmed to increase T-cell apoptosis in vitro and in vivo and to protect tumour cells from being killed, which unlocked the door of T-cell-based cancer immunotherapy [9].

Immunotherapy of pancreatic cancer

In the era of personalized medicine, pancreatic cancer remains an incurable disease because an intrinsic genomic instability results in the escape of cancer cells from chemoradiotherapy or targeted therapies [20]. Because of the unsatisfactory response rates of pancreatic cancer and a tendency for resistance to current standard therapies, including surgery, radiation and chemotherapy, immunotherapy has been emerging as the fourth cornerstone of pancreatic cancer treatment, but is secondary to

Development of targeting PD-1/PD-L1 in pancreatic cancer

Based on the previous introduction on PD-1/PD-L1, therapy targeting PD-1/PD-L1 in pancreatic cancer showed no apparent therapeutic effects. The majority of pancreatic cancers, with the exception of mismatch repair deficiencies, are regarded as immune-quiescent or resistant tumours and are non-responsive to single-checkpoint blockade therapies, such as anti-PD-1/PD-L1 and anti-CTLA-4 antibodies [32]. However, some advances still have been achieved in anti-PD-1/PD-L1 treatment of pancreatic

Underlying mechanisms of single anti-PD-1/PD-L1 immunotherapy failure

It is currently speculated that the efficacy of a single PD-1/PD-L1 blockade may be limited for two primary reasons. First, immunosuppression caused by a high tumour burden is a reason why pancreatic cancer cannot be cured by PD-1/PD-L1 blockade alone. Second, pancreatic cancer is intrinsically non-immunogenic [38].

Overcoming resistance to PD-1/PD-L1 targeted immunotherapy

The previous insights emphasize that it is vital to overcome the resistance of pancreatic cancer to PD-1/PD-L1 targeted immunotherapy. A full awareness of the underlying mechanisms of single anti-PD-1/PD-L1 immunotherapy failure will contribute to the evaluation and prediction of the immune response to anti-PD-1/PD-L1 immunotherapy, which is focused on the immunoediting process and the identification of the type of the anti-cancer immunity, TME and immune resistance. It has been suggested that

Prospect and conclusions

As discussed previously, the efficacy of an anti-PD-1/PD-L1 monotherapy may be limited for the suppressive immune system caused by a high tumour burden and the intrinsic non-immunogenic nature of pancreatic cancer. Because of the non-inflamed phenotype, the non-type Ⅰ TME, and the immune resistance properties of pancreatic cancer, overcoming these characteristics with specific agents will contribute to improving the efficacy of anti-PD-1/PD-L1 immunotherapy.

Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (No. 81272484); Major State Basic Research Development Program of China (973 Program, No.2014CB542300); National Science & Technology Pillar Program during the Twelfth Five-year Plan Period (No.2014BAI09B11); CAMS Innovation Fund for Medical Sciences (CIFMS) (No.2016-I2M-1-001) and CAMS Central Public Welfare Research Institutes Fund for Basic science.

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    These authors contributed equally to this study.

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