A new study from researchers focusing on pancreatic cancer has shown that a new scoring system can provide a single numerical value that reflects whether the tumour microenvironment, the biological “neighbourhood” surrounding a tumour, is working to suppress or support that tumour.

The results of the laboratory study could ultimately help clinicians improve treatment offered to patients with pancreatic cancer.

The new tool, the Harmonic Output of Stromal Traits Factor (HOST-Factor), is a first-of-its-kind composite scoring system that quantifies the functional state of the tumour microenvironment in pancreatic cancer.

Demonstrating Effectiveness of PLDR Chemoradiation

In the study, Fox Chase researchers used HOST-Factor to demonstrate the effectiveness of pulsed low-dose-rate (PLDR) chemoradiation in the treatment of local pancreatic cells in the vicinity of the cancer cells.

Whereas standard chemoradiation pushes these tumour microenvironment cells toward a tumour-promoting state, the HOST-Factor indicated that PLDR chemoradiation stimulated the tumour microenvironment and shifted it toward a tumour-restricting state.

“The HOST-Factor is essentially a way to stage the neighbourhood — the microenvironment — rather than just staging the cancer itself,” said senior author Edna “Eti” Cukierman, PhD, Founding Director of the Marvin and Concetta Greenberg Pancreatic Cancer Institute and Co-Leader of the Cancer Signalling and Microenvironment Research Programme at Fox Chase.

“In pancreatic cancer, most of the tumour mass is made up of non-cancer material. The HOST-Factor gives us a single, quantitative number to understand whether that neighbourhood is working for the patient or against them,” added Cukierman.

She conducted the study with co-lead authors Janusz Franco-Barraza, MD, PhD, an Assistant Research Professor and Manager of the Spatial Immuno-Proteomics Initiative at the Histopathology Facility, and Mariia Dmitrieva, BS, MS, a Research Scientist in the Cukierman Lab, as well as other Fox Chase researchers.

The Challenge of Predicting Disease Behaviour

Pancreatic ductal adenocarcinoma (PDAC), which accounts for over 90% of pancreatic cancer cases, possesses a dense, fibrous tumour microenvironment that is largely made up of cancer-associated fibroblasts (CAFs), which are specialised cells that generate a collagenous scaffolding called the extracellular matrix (ECM).

Normally, in the absence of cancer, these type of fibroblastic cells and their natural scaffolding work together as functional units that suppresses tumour growth. But upon cancer onset, many CAFs and their ECM shift into a tumour-supportive state.

This shift fuels cancer progression, protects the cancer from treatment, and maintains the immune-suppressed niches, which together create pathways for the growth and spread of the cancer.

For years, researchers have worked to understand which features of this microenvironment predict disease behaviour.

One major challenge was that no single biological marker, on its own, could reliably predict the various patient-harvested CAF/ECM units’ tumour-suppressiveness or tumour-supportiveness.

This is the obstacle Cukierman and her team overcame with the HOST-Factor.

Key Findings

• The HOST-Factor reliably measures changes in the state of the tumour microenvironment. The HOST-Factor integrates various established biological markers of CAF and ECM function into a single composite value that, in this study, detected significant treatment-induced changes that no individual marker could identify on its own.
• PLDR chemoradiation shifts the microenvironment toward an anti-tumour state. In in vitro models, human pancreatic CAF/ECM units treated with PLDR-based chemoradiation generated scaffolds that lost their ability to sustain tumour-promoting fibroblast activation. Results showed an approximately two-fold reduction compared to conventional chemoradiation.

Building Toward Clinical Application

The laboratory findings in this study motivated and support a phase I clinical trial at Fox Chase being led by Joshua Meyer, MD, FASTRO, Director of the Marvin and Concetta Greenberg Pancreatic Cancer Institute, Vice Chair of Translational Research, Professor in the Department of Radiation Oncology, and a coauthor on the HOST-Factor study.

The fully enrolled trial assessed the safety of escalated radiotherapy doses delivered with PLDR to patients with pancreatic cancer that could be treated surgically.

The research team is now applying HOST-Factor analysis to pre- and post-treatment patient samples from that study, including as a more comprehensive approach to other tumour microenvironment neighbours besides CAFs, with results to be reported in a future study. “This paper is chapter one of a larger story,” said Cukierman.

“The HOST-Factor lets us ask, ‘Is the microenvironment working for or against our patients? And is our treatment changing that?’ The clinical trial will let us answer those questions and represents a further step in refining the HOST-Factor as a future clinical diagnostic tool in pancreatic as well as numerous other solid cancers.”

The study, “Pulsed Low-Dose-Rate Chemoradiation Induces Stromal Reprogramming in Pancreatic CAF-Generated ECM: Quantification by the HOST-Factor,” was published in Gastro Hep Advances.

Article: Pulsed Low-Dose-Rate Chemoradiation Induces Stromal Reprogramming in Pancreatic CAF-Generated ECM: Quantification by the HOST-Factor

Source: Temple University Health System