The Immune Microenvironment in Pancreatic Cancer

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Abstract

The biology of solid tumors is strongly determined by the interactions of cancer cells with their surrounding microenvironment. In this regard, pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) represents a paradigmatic example for the multitude of possible tumor–stroma interactions. PDAC has proven particularly refractory to novel immunotherapies, which is a fact that is mediated by a unique assemblage of various immune cells creating a strongly immunosuppressive environment in which this cancer type thrives. In this review, we outline currently available knowledge on the cross-talk between tumor cells and the cellular immune microenvironment, highlighting the physiological and pathological cellular interactions, as well as the resulting therapeutic approaches derived thereof. Hopefully a better understanding of the complex tumor–stroma interactions will one day lead to a significant advancement in patient care.

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Most cited references 239

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Cancer statistics, 2020

Rebecca Siegel, Kimberly D Miller, Ahmedin Jemal (2020)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.

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PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

Dung Le, Jennifer Uram, Hao Wang … (2015)

Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.

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Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

F. Stephen Hodi, Steven J O'Day, David F McDermott … (2010)

An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

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Author and article information

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 03 October 2020

Publication date Collection: October 2020

Volume: 21

Issue: 19

Electronic Location Identifier: 7307

Affiliations

[1 ]Institute for Medical Microbiology and Hospital Hygiene, Philipps University Marburg, 35043 Marburg, Germany; magdalena.huber@ 123456staff.uni-marburg.de

[2 ]Institute of Pathology, University Hospital Giessen-Marburg, 35043 Marburg, Germany; brehmc@ 123456med.uni-marburg.de

[3 ]Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, Center for Tumor- and Immunology (ZTI), Philipps University Marburg, 35043 Marburg, Germany; gress@ 123456med.uni-marburg.de (T.M.G.); malte.buchholz@ 123456staff.uni-marburg.de (M.B.); christian.bauer@ 123456med.uni-marburg.de (C.B.)

[4 ]Institute for Tumor Immunology, Clinic for Hematology, Oncology and Immunology, Center for Tumor Biology and Immunology (ZTI), Philipps University Marburg, 35043 Marburg, Germany; poggevon@ 123456staff.uni-marburg.de (E.P.v.S.); bilal.alashkaralhamwe@ 123456uni-marburg.de (B.A.A.)

[5 ]Department of Visceral-, Thoracic- and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany; slater@ 123456med.uni-marburg.de

[6 ]Department of Neurosurgery, Philipps University Marburg, Baldingerstrasse, 35043 Marburg, Germany; jbartsch@ 123456med.uni-marburg.de

Author notes

[* ]Correspondence: lauth@ 123456staff.uni-marburg.de ; Tel.: +49-6421-286-6727

Author information

Magdalena Huber https://orcid.org/0000-0002-2963-0693

Corinna U. Brehm https://orcid.org/0000-0002-4312-1377

Thomas M. Gress https://orcid.org/0000-0002-9333-5461

Jörg W. Bartsch https://orcid.org/0000-0002-2773-3357

Article

Publisher ID: ijms-21-07307

DOI: 10.3390/ijms21197307

PMC ID: 7583843

PubMed ID: 33022971

SO-VID: fe741e2a-0171-4440-8665-93a708c2e1f6

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

History

Date received : 08 September 2020

Date accepted : 29 September 2020

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The Immune Microenvironment in Pancreatic Cancer

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Most cited references 239

Cancer statistics, 2020

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

Improved Survival with Ipilimumab in Patients with Metastatic Melanoma

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