expert roundtables

Overcoming the Immunosuppressive Tumor Microenvironment in Metastatic Pancreatic Cancer

by Thomas A. Abrams, MD, Alok Khorana, MD, Michael Morse, MD, MHS, FACP

Overview

The incidence of metastatic pancreatic cancer has increased over the past several decades, and it now ranks as the fourth leading cause of cancer death in the United States. Despite the high mortality rate, there is optimism surrounding improved outcomes with newly developed treatment regimens. Our featured experts in the field discuss newly approved treatment options for metastatic pancreatic cancer and the role of the immunosuppressive tumor microenvironment in the treatment of pancreatic cancer.

Q:

Does the immunosuppressive tumor microenvironment in pancreatic cancer lead to the poor outcomes that are observed? Could the development of mechanobiology-targeted therapeutic approaches assist in overcoming anticancer drug resistance in metastatic pancreatic cancer?

Michael Morse, MD, MHS, FACP

Professor of Medicine, Division of Medical Oncology
Professor, Department of Surgery
Duke University Medical Center
Durham, NC

Why are pancreatic cancers so resistant to therapy, chemotherapies, targeted therapies, and immunotherapy? First, from the immunotherapy standpoint, it does seem to have something to do with the stroma. It certainly is an environment where it is difficult for immune cells to actually penetrate into the tumor. Second, there are suppressive cell populations, particularly myeloid-derived suppressor cells, and also regulatory T cells and TH2 cells, in that environment contributing to an immunosuppressive cytokine environment. So, clearly there are a number of reasons why the immune system does not respond to the pancreatic cancer. I think the third issue is that when you talk about the stroma, it is not just that the stroma creates a barrier, it is also that the stroma is alive. There is certainly a lot of fibrotic tissue, but there are cells within that fibrotic tissue, fibroblasts, that secrete cytokines that are favorable for the survival of the pancreatic cancer. The cytokines allow the pancreatic cancer cells to sort of resist dying in response to therapies that are delivered. The challenge is not just disrupting that fibrotic barrier, the desmoplasia, in the tumor but also disrupting the interplay between the cells in that stroma and the pancreatic cancer cells that support each other.

Thomas A. Abrams, MD

Assistant Professor of Medicine
Harvard Medical School
Senior Physician
Dana-Farber Cancer Institute
Boston, MA

The stroma obviously plays a gigantic role in how difficult it is to treat the pancreas cancer, and it is not just a barrier. There are other kinds of cells playing a role, and that interplay is incredibly complicated. As we peel back the layers, we realize the cellular interactions are things that we potentially may be able to target to treat the disease. One thing that we are trying to do is to figure out ways to turn what is a cold tumor –  immunologically, pancreatic cancer being a very cold – tumor into something that would be something hot that we can really target with immunotherapy. Combining the current PD1 inhibitors with drugs that can target the stroma may be a potential avenue to accomplishing that, but right now, it is in the investigational phase. The immunosuppressive tumor microenvironment is of critical importance. There is no question that it is playing a role in the virulence of this disease. If we can find a way around it, I think we will have a lot of different treatment avenues that are currently unavailable to us.

"As we peel back the layers, we realize the cellular interactions are things that we potentially may be able to target to treat the disease."

Thomas Abrams, MD

Alok Khorana, MD

Professor of Medicine
Director, Gastrointestinal Malignancies Program
Cleveland Clinic
Cleveland, OH

There is no question that pancreatic cancer is a really tough cancer to treat. It is very primarily chemo-resistant. Many clinical trials in pancreatic cancer have failed. They are primarily the trials that have used traditional cytotoxic therapy. More recent trials have used novel drug delivery mechanisms, such as nanoliposomal irinotecan or nanoparticles of paclitaxel, and that has certainly allowed us to overcome some of this issue. We still need to understand a lot more about how the immune response is involved in tumorigenesis in patients with pancreatic cancer. The recent approval of pembrolizumab for patients with microsatellite instability high solid tumors is an example of utilizing the body’s immune mechanisms to facilitate immune therapy. Some data from recent preclinical and basic science laboratories show that molecules such as AREG 3G can function as an immunosuppressive promoter that weakens tumor-specific antigenicity and suppresses antitumor effects of CD8-positive T cells in animal models of pancreatic cancer. Overcoming the immunosuppressive microenvironments with both existing treatments and new treatments that could overcome some of these effects is widely anticipated and will hopefully change the way we treat pancreatic cancer in the future.

"More recent trials have used novel drug delivery mechanisms, such as nanoliposomal irinotecan or nanoparticles of paclitaxel, and that has certainly allowed us to overcome some of this issue."

Alok Khorana, MD

References

Ansari D, Gustafsson A, Andersson R. Update on the management of pancreatic cancer: surgery is not enough. World J Gastroenterol. 2015;21(11):3157-3165.

Coppola S, Carnevale I, Danen EHJ, et al. A mechanopharmacology approach to overcome chemoresistance in pancreatic cancer. Drug Resist Updat. 2017;31:43-51.

Liu X, Zhou Z, Cheng Q, et al. Acceleration of pancreatic tumorigenesis under immunosuppressive microenvironment induced by Reg3g overexpression. Cell Death Dis. 2017;8(9):e3033.

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