Review

. 2022 Feb 9;41(1):56.

doi: 10.1186/s13046-022-02273-w.

Combination therapy for pancreatic cancer: anti-PD-(L)1-based strategy

Lingyue Liu^#^{1

2}, Xing Huang^#^{1

2

3}, Fukang Shi^{1

2}, Jinyuan Song^{1

2}, Chengxiang Guo^{1

2}, Jiaqi Yang^{1

2

3

4

5}, Tingbo Liang^{6

7

8

9

10}, Xueli Bai^{11

12

13

14

15}

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79# Qingchun Road, Hangzhou, 310003, Zhejiang, China.
² Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
³ Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
⁴ The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009, Zhejiang, China.
⁵ Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, Zhejiang, China.
⁶ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79# Qingchun Road, Hangzhou, 310003, Zhejiang, China. liangtingbo@zju.edu.cn.
⁷ Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China. liangtingbo@zju.edu.cn.
⁸ Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China. liangtingbo@zju.edu.cn.
⁹ The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009, Zhejiang, China. liangtingbo@zju.edu.cn.
¹⁰ Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, Zhejiang, China. liangtingbo@zju.edu.cn.
¹¹ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79# Qingchun Road, Hangzhou, 310003, Zhejiang, China. shirleybai@zju.edu.cn.
¹² Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China. shirleybai@zju.edu.cn.
¹³ Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China. shirleybai@zju.edu.cn.
¹⁴ The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009, Zhejiang, China. shirleybai@zju.edu.cn.
¹⁵ Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, Zhejiang, China. shirleybai@zju.edu.cn.

^# Contributed equally.

PMID: 35139879
PMCID: PMC8827285
DOI: 10.1186/s13046-022-02273-w

Review

Combination therapy for pancreatic cancer: anti-PD-(L)1-based strategy

Lingyue Liu et al. J Exp Clin Cancer Res. 2022.

. 2022 Feb 9;41(1):56.

doi: 10.1186/s13046-022-02273-w.

Authors

Lingyue Liu^#^{1

2}, Xing Huang^#^{1

2

3}, Fukang Shi^{1

2}, Jinyuan Song^{1

2}, Chengxiang Guo^{1

2}, Jiaqi Yang^{1

2

3

4

5}, Tingbo Liang^{6

7

8

9

10}, Xueli Bai^{11

12

13

14

15}

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79# Qingchun Road, Hangzhou, 310003, Zhejiang, China.
² Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China.
³ Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
⁴ The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009, Zhejiang, China.
⁵ Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, Zhejiang, China.
⁶ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79# Qingchun Road, Hangzhou, 310003, Zhejiang, China. liangtingbo@zju.edu.cn.
⁷ Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China. liangtingbo@zju.edu.cn.
⁸ Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China. liangtingbo@zju.edu.cn.
⁹ The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009, Zhejiang, China. liangtingbo@zju.edu.cn.
¹⁰ Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, Zhejiang, China. liangtingbo@zju.edu.cn.
¹¹ Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79# Qingchun Road, Hangzhou, 310003, Zhejiang, China. shirleybai@zju.edu.cn.
¹² Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China. shirleybai@zju.edu.cn.
¹³ Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China. shirleybai@zju.edu.cn.
¹⁴ The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310009, Zhejiang, China. shirleybai@zju.edu.cn.
¹⁵ Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, Zhejiang, China. shirleybai@zju.edu.cn.

^# Contributed equally.

PMID: 35139879
PMCID: PMC8827285
DOI: 10.1186/s13046-022-02273-w

Abstract

Mortality associated with pancreatic cancer is among the highest of all malignancies, with a 5-year overall survival of 5-10%. Immunotherapy, represented by the blocking antibodies against programmed cell death protein 1 or its ligand 1 (anti-PD-(L)1), has achieved remarkable success in a number of malignancies. However, due to the immune-suppressive tumor microenvironment, the therapeutic efficacy of anti-PD-(L)1 in pancreatic cancer is far from expectation. To address such a fundamental issue, chemotherapy, radiotherapy, targeted therapy and even immunotherapy itself, have individually been attempted to combine with anti-PD-(L)1 in preclinical and clinical investigation. This review, with a particular focus on pancreatic cancer therapy, collects current anti-PD-(L)1-based combination strategy, highlights potential adverse effects of accumulative combination, and further points out future direction in optimization of combination, including targeting post-translational modification of PD-(L)1 and improving precision of treatment.

Keywords: Combinational therapy; Immune checkpoint inhibitor; PD-1; PD-L1; Pancreatic cancer; Post-translational modification; Precision therapy; Systematic treatment.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1**
Pancreatic cancer targeted therapies described in the review. ①nivolumab, pembrolizumab, toripalimab; ②durvalumab, avelumab, atezolizumab; ③PEGPH20; ④paricalcitol; ⑤galunisertib, M7824, LY2157299; ⑥cabiralizumab, lacnotuzumab; ⑦APX005M; ⑧BL-8040, AMD3100; ⑨NOX-A12; ⑩SX-682; ⑪defactinib; ⑫acalabrutinib; ⑬niraparib, BGB-290. BTK: Bruton’s tyrosine kinase; CAF: carcinoma-associated fibroblast; CSF1R: colony stimulating factor 1; CXCL12: CXC-chemokine ligand 12; CXCR2: CXC-chemokine receptor 2; CXCR4: CXC-chemokine receptor 4; FAK: focal adhesion kinase; FAP: fibroblast activation protein; HA: hyaluronic acid; HMGB1: high-mobility group protein B1; IL-6R: interleukin-6 receptor; MDSC: myeloid-derived suppressor cell; PARP: Poly (ADP-ribose) polymerase; PC: pancreatic cancer; PD-1: programmed cell death protein 1; PD-L1: programmed cell death ligand 1; PSC: pancreatic stellate cell; PSC*: activated pancreatic stellate cell; TAM: tumor-associated macrophage; TGFβR: transforming growth factor-β receptor; VDR: vitamin D receptor

**Fig. 2**
Post-translational modifications of PD-L1 described in the review. AMPK: adenosine-5′-monophosphate-activated protein kinase; B3GNT3: β-1,3-N-acetylglucosaminyl transferase; CSN5: COP9 signalosome complex subunit 5; EGFR: epidermal growth factor receptor; FKBP51: FK506 binding protein 51; GSK3β: glycogen synthase kinase 3β; IL6R: interleukin-6 receptor; JAK1: Janus kinase 1; PD-L1: programmed cell death ligand 1; Sigma1: sigma nonopioid intracellular receptor 1; SPOP: speckle-type POZ protein; STT3: staurosporine temperature sensitivity 3; STUB1: STIP1 homology and U-box containing protein 1; USP22: ubiquitin-specific protease 22; ZDHHC3: zinc-finger DHHC-type-containing 3; β-TrCP: β-transducin repeat-containing protein

See this image and copyright information in PMC

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. - PubMed
1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7–33. - PubMed
1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913–2921. - PubMed
1. Grossberg AJ, Chu LC, Deig CR, Fishman EK, Hwang WL, Maitra A, et al. Multidisciplinary standards of care and recent progress in pancreatic ductal adenocarcinoma. CA Cancer J Clin. 2020. - PMC - PubMed
1. Mizrahi JD, Surana R, Valle JW, Shroff RT. Pancreatic cancer. Lancet. 2020;395(10242):2008–2020. - PubMed

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Combination therapy for pancreatic cancer: anti-PD-(L)1-based strategy

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Combination therapy for pancreatic cancer: anti-PD-(L)1-based strategy

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Conflict of interest statement

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