Top

Journal of Gastrointestinal Cancer

Published in:

01-03-2019 | Review Article

Pancreatic Cancer and Immunotherapy: Resistance Mechanisms and Proposed Solutions

Authors: Elaine Tan, Bassel El-Rayes

Published in: Journal of Gastrointestinal Cancer | Issue 1/2019

Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) continues to be one of the most aggressive and lethal diseases in the world. The success of immunotherapy in other types of malignancy has led to further trials to understand better the role of immunotherapy in PDAC. However, initial studies with immunotherapy, namely, the checkpoint inhibitors, in PDAC have not been met with the same outcomes. The purpose of this review is to identify and discuss the various resistance mechanisms of PDAC to immunotherapy (pancreatic stroma, genetic predisposition/epigenetics, and the immune inhibitory cells, cytokines, soluble factors, and enzymes that comprise the tumor microenvironment) and the solutions currently being studied to overcome them.

Conclusions

Various preclinical and early clinical studies have shown that immunotherapy, especially checkpoint inhibitors, in PDAC may be efficacious as part of a multi-modal treatment, in combination with other therapies that target these resistance mechanisms. Several clinical trials are ongoing to explore this concept further.

Thind K, Padrnos LJ, Ramanathan RK, et al. Immunotherapy in pancreatic cancer treatment: a new frontier. Ther Adv Gastroenterol. 2017;10(1):168–94.CrossRef

Walker EJ, Kho AH. Beyond first-line chemotherapy for advanced pancreatic cancer: an expanding array of therapeutic options? J Immunother. 2010;33(8):828–33.CrossRef

Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817–25.CrossRefPubMed

Von Hoff D, Ervin T, Arena F, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–703.CrossRef

Ibrahim AM, Wang YH. Viro-immune therapy: a new strategy for treatment of pancreatic cancer. World J Gastroenterol. 2016;22(2):748–63.CrossRefPubMedPubMedCentral

Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33(8):828–33.CrossRefPubMedPubMedCentral

Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.CrossRefPubMedPubMedCentral

Duluc C, Moatassim-Billah S, Chalabi-Dchar M. Pharmacological targeting of the protein synthesis mTOR/4E-BP1 pathway in cancer-associated fibroblasts abrogates pancreatic tumor chemoresistance. EMBO Mol Med. 2015;7(6):735–53.CrossRefPubMedPubMedCentral

Hartmann N, Giese NA, Giese T, et al. Prevailing role of contact guidance in intrastromal T-cell trapping in human pancreatic cancer. Clin Cancer Res. 2014;20(13):3422–33.CrossRefPubMed

10.

Mei L, Du W, Ma WW. Targeting stromal microenvironment in pancreatic ductal adenocarcinoma: controversies and promises. J Gastrointest Oncol. 2016;7(3):487–94.CrossRefPubMedPubMedCentral

11.

Jiang H, Hegde S, Knolhoff BL, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 2016;22(8):851–60.CrossRefPubMedPubMedCentral

12.

Bynigeri RR, Jakkampudi A, Jangala R, et al. Pancreatic stellate cell: Pandora’s box for pancreatic disease biology. World J Gastroenterol. 2017;23(3):382–405.CrossRefPubMedPubMedCentral

13.

Bahrami A, Khazaei M, Bagherieh F, Ghayour-Mobarhan M, et al. Targeting stroma in pancreatic cancer: promises and failures of targeted therapies. J Cell Physiol. 2017;232(11):2931–7.CrossRefPubMed

14.

Wong KM, Horton KJ, Coveler AL, et al. Targeting the tumor stroma: the biology and clinical development of pegylated recombinant human hyaluronidase (PEGPH20). Curr Oncol Rep. 2017;19(7):47.CrossRefPubMed

15.

Hugo W, Zaretsky JM, Sun L, Song C, et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell. 2016;165(1):35–44.CrossRefPubMedPubMedCentral

16.

Peng W, Chen JQ, Liu C, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 2016;6(2):202–16.CrossRefPubMed

17.

Khan KH, Yap TA, Yan L, et al. Targeting the PI3K-AKT-mTOR signaling network in cancer. Chin J Cancer. 2013;32(5):253–65.CrossRefPubMedPubMedCentral

18.

Ding G, Zhou L, Qian Y, et al. Pancreatic cancer-derived exosomes transfer miRNAs to dendritic cells and inhibit RFXAP expression via miR-212-3p. Oncotarget. 2015;6(30):29877–88.CrossRefPubMedPubMedCentral

19.

Sharma P, Hu-Lieskovan S, Wargo JA, et al. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168(4):707–23.CrossRefPubMedPubMedCentral

20.

Skelton RA, Javed A, Zheng L, et al. Overcoming the resistance of pancreatic cancer to immune checkpoint inhibitors. J Surg Oncol. 2017;116(1):55–62.CrossRefPubMed

21.

Amedei A, Niccolai E, Prisco D. Pancreatic cancer: role of the immune system in cancer progression and vaccine-based immunotherapy. Hum Vaccin Immunother. 2014;10(11):3354–68.CrossRefPubMedPubMedCentral

22.

Johnson BA III, Yarchoan M, Lee V, et al. Strategies for increasing pancreatic tumor immunogenicity. Clin Cancer Res. 2017;23(7):1656–69.CrossRefPubMedPubMedCentral

23.

Steele CW, Karim SA, Leach JDG, et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell. 2016;29(6):832–45.CrossRefPubMedPubMedCentral

24.

Seo YD, Pillarisetty VG. T-cell programming in pancreatic adenocarcinoma: a review. Cancer Gene Ther. 2017;24(3):106–13.CrossRefPubMed

25.

Mace TA, Shakya R, Pitarresi JR, et al. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut. 2018;67(2):320–32.CrossRefPubMed

26.

McAllister F, Leach SD. Targeting IL-17 for pancreatic cancer prevention. Oncotarget. 2014;5(20):9530–1.CrossRefPubMedPubMedCentral

27.

Wolpin BM, Hezel AF, Abrams T, et al. Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer. J Clin Oncol. 2009;27:193–8.CrossRefPubMedPubMedCentral

28.

Javle MM, Shroff RT, Xiong H, et al. Inhibition of the mammalian target of rapamycin (mTOR) in advanced pancreatic cancer: results of two phase II studies. BMC Cancer. 2010;10:368.CrossRefPubMedPubMedCentral

29.

Hingorani SR, Harris WP, Beck JT, et al. Phase Ib study of PEGylated recombinant human hyaluronidase and gemcitabine in patients with advanced pancreatic cancer. Clin Cancer Res. 2016;22:2848–54.CrossRefPubMedPubMedCentral

30.

Zeitz U, Weber K, Soegiarto DW, et al. Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor. FASEB J. 2003;17:509–11.CrossRefPubMed

31.

Sherman M, Yu R, Dannielle D, et al. Vitamin D receptor mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 2014;159(1):80–93.CrossRefPubMedPubMedCentral

32.

Beatty GL, Chiorean EG, Fishman MP, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331(6024):1612–6.CrossRefPubMedPubMedCentral

33.

Beatty GL, Torigian DA, Chiorean EG, et al. A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res. 2013;19(22):6286–95.CrossRefPubMed

34.

Okkenhaug K, Graupera M, Vanhaesebroeck B. Targeting PI3K in cancer: impact on tumor cells, their protective stroma, angiogenesis, and immunotherapy. Cancer Discov. 2016;6(10):1090–105.CrossRefPubMedPubMedCentral

35.

Kaneda MM, Cappello P, Nguyen AV, et al. Macrophage PI3Kγ drives pancreatic ductal adenocarcinoma progression. Cancer Discov. 2016;6(8):870–85.CrossRefPubMedPubMedCentral

36.

Bahary N, Garrido-Laguna I, Cinar P, et al. Phase 2 trial of the indoleamine 2,3-dioxygenase pathway (IDO) inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of metastatic pancreas cancer: interim analysis. J Clin Oncol. 34(15):3020.

37.

Zhu Y, Knolhoff BL, Meyer MA, et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res. 2014;74(18):5057–69.CrossRefPubMedPubMedCentral

38.

Ferrantini M, Capone I, Belardelli F. Interferon-alpha and cancer: mechanisms of action and new perspectives of clinical use. Biochimie. 2007;89:884–93.CrossRefPubMed

39.

Hara H, Kobayashi A, Narumi K, et al. Intratumoral interferon-alpha gene transfer enhances tumor immunity after allogeneic hematopoietic stem cell transplantation. Cancer Immunol Immunother. 2009;58:1007–21.CrossRefPubMed

40.

Narumi K, Udagawa T, Kondoh A, et al. In vivo delivery of interferon-alpha gene enhances tumor immunity and suppresses immunotolerance in reconstituted lymphopenic hosts. Gene Ther. 2012;19:34–48.CrossRefPubMed

41.

Aida K, Miyakawa R, Suzuki K, et al. Suppression of Tregs by anti-glucocorticoid induced TNF receptor antibody enhances the antitumor immunity of interferon-α gene therapy for pancreatic cancer. Cancer Sci. 2014 Feb;105(2):159–67.CrossRefPubMedPubMedCentral

Title: Pancreatic Cancer and Immunotherapy: Resistance Mechanisms and Proposed Solutions
Authors: Elaine Tan
Bassel El-Rayes
Publication date: 01-03-2019
Publisher: Springer US
Published in: Journal of Gastrointestinal Cancer / Issue 1/2019
Print ISSN: 1941-6628
Electronic ISSN: 1941-6636
DOI: https://doi.org/10.1007/s12029-018-0179-z

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Pancreatic Cancer and Immunotherapy: Resistance Mechanisms and Proposed Solutions

Abstract

Background

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2019

A Deregulated PI3K-AKT Signaling Pathway in Patients with Colorectal Cancer

Differential Diagnosis of Pancreatic Epidermoid Cyst Without a Solid Component (Residual Splenic Tissue) vs. Mucinous Cystic Neoplasm

Role of VEGF, CD105, and CD31 in the Prognosis of Colorectal Cancer Cases

Progression-Free Survival in Patients Receiving Chemotherapy Alone (C) or Chemotherapy with Bevacizumab (CB) for First-Line Treatment of KRAS Mutant Metastatic Colorectal Cancer in Community Oncology Settings

A Real-World Comparison of FOLFIRINOX, Gemcitabine Plus nab-Paclitaxel, and Gemcitabine in Advanced Pancreatic Cancers

Regulatory Fluctuation of WNT16 Gene Expression Is Associated with Human Gastric Adenocarcinoma

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page