Challenges and Opportunities for Pancreatic Cancer Immunotherapy

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2020 Sep 18

PMID 32946773

Citations 254

Authors

Adham S Bear

Robert H Vonderheide

Mark H OHara

Affiliations

Soon will be listed here.

Abstract

Pancreatic ductal adenocarcinoma (PDA) is among the most immune-resistant tumor types. Its unique genomic landscape shaped by oncogenic drivers promotes immune suppression from the earliest stages of tumor inception to subvert adaptive T cell immunity. Single-agent immune modulators have thus far proven clinically ineffective, and multi-modal therapies targeting mechanisms of immunotherapy resistance are likely needed. Here, we review novel immunotherapy strategies currently under investigation to (1) confer antigen specificity, (2) enhance T cell effector function, and (3) neutralize immunosuppressive elements within the tumor microenvironment that may be rationally combined to untangle the web of immune resistance in PDA and other tumors.

Citing Articles

Mesothelin (MSLN) is Highly Expressed in Triple Negative Breast Cancer and is Associated with Enhanced Cell Proliferation and Proinflammatory Tumor Microenvironment.

Hagerty B, Sato T, Wu R, Ishikawa T, Takabe K Ann Surg Oncol. 2025; .

PMID: 40080368 DOI: 10.1245/s10434-025-17117-y.

Targeting the NPY/NPY1R signaling axis in mutant p53-dependent pancreatic cancer impairs metastasis.

Chambers C, Watakul S, Schofield P, Howell A, Zhu J, Tran A Sci Adv. 2025; 11(11):eadq4416.

PMID: 40073121 PMC: 11900870. DOI: 10.1126/sciadv.adq4416.

PD-1 transcriptomic landscape across cancers and implications for immune checkpoint blockade outcome.

Chen H, Kim N, Nishizaki D, Nesline M, Conroy J, DePietro P NPJ Genom Med. 2025; 10(1):21.

PMID: 40069238 PMC: 11897377. DOI: 10.1038/s41525-025-00465-9.

A novel signature predicts prognosis in pancreatic cancer based on tumor membrane-associated genes.

Ding Z, Wu J, Ye Y, Zhong Y, Yan L, Wang P Heliyon. 2025; 11(4):e42791.

PMID: 40066030 PMC: 11891719. DOI: 10.1016/j.heliyon.2025.e42791.

Injectable celastrol-loading emulsion hydrogel for immunotherapy of low-immunogenic cancer.

Liu Y, Zhang J, Lai C, Wang W, Huang Y, Bao X J Nanobiotechnology. 2025; 23(1):183.

PMID: 40050985 PMC: 11887069. DOI: 10.1186/s12951-025-03154-y.

References

Gustafson C, Jadhav R, Cao W, Qi Q, Pegram M, Tian L . Immune cell repertoires in breast cancer patients after adjuvant chemotherapy. JCI Insight. 2020; 5(4). PMC: 7101137. DOI: 10.1172/jci.insight.134569. View

Sharma P, Hu-Lieskovan S, Wargo J, Ribas A . Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell. 2017; 168(4):707-723. PMC: 5391692. DOI: 10.1016/j.cell.2017.01.017. View

Le D, Wang-Gillam A, Picozzi V, Greten T, Crocenzi T, Springett G . Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol. 2015; 33(12):1325-33. PMC: 4397277. DOI: 10.1200/JCO.2014.57.4244. View

Le D, Lutz E, Uram J, Sugar E, Onners B, Solt S . Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother. 2013; 36(7):382-9. PMC: 3779664. DOI: 10.1097/CJI.0b013e31829fb7a2. View

Tran E, Robbins P, Rosenberg S . 'Final common pathway' of human cancer immunotherapy: targeting random somatic mutations. Nat Immunol. 2017; 18(3):255-262. PMC: 6295671. DOI: 10.1038/ni.3682. View

Le D, Picozzi V, Ko A, Wainberg Z, Kindler H, Wang-Gillam A . Results from a Phase IIb, Randomized, Multicenter Study of GVAX Pancreas and CRS-207 Compared with Chemotherapy in Adults with Previously Treated Metastatic Pancreatic Adenocarcinoma (ECLIPSE Study). Clin Cancer Res. 2019; 25(18):5493-5502. PMC: 7376746. DOI: 10.1158/1078-0432.CCR-18-2992. View

Carreno B, Magrini V, Becker-Hapak M, Kaabinejadian S, Hundal J, Petti A . Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science. 2015; 348(6236):803-8. PMC: 4549796. DOI: 10.1126/science.aaa3828. View

Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky J, Desrichard A . Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014; 371(23):2189-2199. PMC: 4315319. DOI: 10.1056/NEJMoa1406498. View

Simnica D, Akyuz N, Schliffke S, Mohme M, V Wenserski L, Mahrle T . T cell receptor next-generation sequencing reveals cancer-associated repertoire metrics and reconstitution after chemotherapy in patients with hematological and solid tumors. Oncoimmunology. 2019; 8(11):e1644110. PMC: 6791461. DOI: 10.1080/2162402X.2019.1644110. View

10.

Steele C, Karim S, Leach J, Bailey P, Upstill-Goddard R, Rishi L . CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2016; 29(6):832-845. PMC: 4912354. DOI: 10.1016/j.ccell.2016.04.014. View

11.

Winograd R, Byrne K, Evans R, Odorizzi P, Meyer A, Bajor D . Induction of T-cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma. Cancer Immunol Res. 2015; 3(4):399-411. PMC: 4390506. DOI: 10.1158/2326-6066.CIR-14-0215. View

12.

Schmid P, Adams S, Rugo H, Schneeweiss A, Barrios C, Iwata H . Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2018; 379(22):2108-2121. DOI: 10.1056/NEJMoa1809615. View

13.

Beatty G, Chiorean E, Fishman M, Saboury B, Teitelbaum U, Sun W . CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011; 331(6024):1612-6. PMC: 3406187. DOI: 10.1126/science.1198443. View

14.

Shima H, Tsurita G, Wada S, Hirohashi Y, Yasui H, Hayashi H . Randomized phase II trial of survivin 2B peptide vaccination for patients with HLA-A24-positive pancreatic adenocarcinoma. Cancer Sci. 2019; 110(8):2378-2385. PMC: 6676125. DOI: 10.1111/cas.14106. View

15.

Linette G, Carreno B . Tumor-Infiltrating Lymphocytes in the Checkpoint Inhibitor Era. Curr Hematol Malig Rep. 2019; 14(4):286-291. PMC: 6642683. DOI: 10.1007/s11899-019-00523-x. View

16.

Weden S, Klemp M, Gladhaug I, Moller M, Eriksen J, Gaudernack G . Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras. Int J Cancer. 2010; 128(5):1120-8. DOI: 10.1002/ijc.25449. View

17.

Kaufman H, Kim-Schulze S, Manson K, DeRaffele G, Mitcham J, Seo K . Poxvirus-based vaccine therapy for patients with advanced pancreatic cancer. J Transl Med. 2007; 5:60. PMC: 2217514. DOI: 10.1186/1479-5876-5-60. View

18.

Blando J, Sharma A, Higa M, Zhao H, Vence L, Yadav S . Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer. Proc Natl Acad Sci U S A. 2019; 116(5):1692-1697. PMC: 6358697. DOI: 10.1073/pnas.1811067116. View

19.

Rizvi N, Hellmann M, Snyder A, Kvistborg P, Makarov V, Havel J . Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015; 348(6230):124-8. PMC: 4993154. DOI: 10.1126/science.aaa1348. View

20.

Zhang Y, Ma J, Zhang H, Jiang Y, Luo W . Cancer vaccines: Targeting KRAS-driven cancers. Expert Rev Vaccines. 2020; 19(2):163-173. DOI: 10.1080/14760584.2020.1733420. View