Collagen depletion by pirfenidone enhances antitumor effect of oncolytic adenovirus against peritoneal metastases of gastric cancer

TL;DR

Pirfenidone reduces collagen in tumors, allowing oncolytic viruses to better fight peritoneal metastases in gastric cancer.

Contribution

Combining pirfenidone with oncolytic adenovirus improves treatment of peritoneal metastases by reducing collagen barriers.

Findings

High collagen levels correlate with peritoneal metastasis and poor gastric cancer prognosis.

Pirfenidone suppresses collagen production and improves oncolytic virus penetration in tumors.

Combining pirfenidone with oncolytic adenovirus enhances antitumor effects in peritoneal metastases.

Abstract

Cancer-associated fibroblasts (CAFs) play a crucial role in collagen accumulation, which develops and promotes peritoneal metastasis (PM) in gastric cancer (GC). In addition, the abundant stromal collagens in the tumor microenvironment function as a physical barrier against penetration of antitumor drugs and oncolytic viruses. This study investigated whether collagen depletion by pirfenidone (PFD), an antifibrotic drug, enhances the antitumor effects of oncolytic adenoviruses. Analysis of the clinical samples revealed a significant association of high expression of collagen 1 and α-smooth muscle actin (α-SMA) with PM development and poor prognosis of advanced GC. Human and murine GC cells enhanced collagen production by fibroblasts, which was suppressed by PFD. Abundant fibroblasts and collagen inhibited the penetration of OBP-702, which reduced the antitumor effects of OBP-702 in the spheroid model. Intraperitoneal co-injection of GC cells and fibroblasts promoted the development of collagen-rich PM and reduced the antitumor effects of OBP-702 in vivo model. PFD suppressed collagen production in PM and improved viral penetration into the tumors, which enhanced the antitumor effects of OBP-702 against PM of GC. Collagen depletion by PFD enhances the penetration of OBP-702 into PM of GC, in turn enhancing the antitumor effects of OBP-702 against PM of GC.

Increased collagen produced by cancer-associated fibroblasts is associated with the resistance to intraperitoneal virotherapy against peritoneal metastasis (PM). The antifibrotic drug, pirfenidone (PFD) suppressed collagen production, and which contributed to enhance the penetration of oncolytic adenovirus into the PM. Intraperitoneal virotherapy combined with PFD might be a promising treatment strategy against PM.

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