Collagenase-Expressing Salmonella Targets Major Collagens in Pancreatic Cancer Leading to Reductions in Immunosuppressive Subsets and Tumor Growth

Ebelt, Nancy D.; Zamloot, Vic; Zuniga, Edith; Passi, Kevin B.; Sobocinski, Lukas J.; Young, Cari A.; Blazar, Bruce R.; Manuel, Edwin R.

doi:10.3390/cancers13143565

Cited by 13 publications

(10 citation statements)

References 70 publications

(81 reference statements)

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“…These changes were associated with significantly improved efficacy of both TIL-based therapy and checkpoint inhibitor therapy ( 181 ). Recently, the use of a bacterial-based agent for delivery of collagenase to murine pancreatic tumors was demonstrated ( 186 ). This approach led to reduced collagen levels in the tumors and, importantly, also to enhanced efficacy of checkpoint inhibitor treatment ( 186 ).…”

Section: The Effects Of Tumor Collagen On Immunotherapymentioning

confidence: 99%

“…Recently, the use of a bacterial-based agent for delivery of collagenase to murine pancreatic tumors was demonstrated ( 186 ). This approach led to reduced collagen levels in the tumors and, importantly, also to enhanced efficacy of checkpoint inhibitor treatment ( 186 ). The ability of collagen to influence immunotherapy could involve DDR2-signaling since treatment of several murine cancer models with a combination of anti-PD-1 antibody and a DDR2-inhibitor led to an increase in CD8 + T cells and a reduced tumor burden ( 187 ).…”

Section: The Effects Of Tumor Collagen On Immunotherapymentioning

confidence: 99%

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Immune Modulatory Properties of Collagen in Cancer

2021

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During tumor growth the extracellular matrix (ECM) undergoes dramatic remodeling. The normal ECM is degraded and substituted with a tumor-specific ECM, which is often of higher collagen density and increased stiffness. The structure and collagen density of the tumor-specific ECM has been associated with poor prognosis in several types of cancer. However, the reason for this association is still largely unknown. Collagen can promote cancer cell growth and migration, but recent studies have shown that collagens can also affect the function and phenotype of various types of tumor-infiltrating immune cells such as tumor-associated macrophages (TAMs) and T cells. This suggests that tumor-associated collagen could have important immune modulatory functions within the tumor microenvironment, affecting cancer progression as well as the efficacy of cancer immunotherapy. The effects of tumor-associated collagen on immune cells could help explain why a high collagen density in tumors is often correlated with a poor prognosis. Knowledge about immune modulatory functions of collagen could potentially identify targets for improving current cancer therapies or for development of new treatments. In this review, the current knowledge about the ability of collagen to influence T cell activity will be summarized. This includes direct interactions with T cells as well as induction of immune suppressive activity in other immune cells such as macrophages. Additionally, the potential effects of collagen on the efficacy of cancer immunotherapy will be discussed.

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Section: The Effects Of Tumor Collagen On Immunotherapymentioning

confidence: 99%

Section: The Effects Of Tumor Collagen On Immunotherapymentioning

confidence: 99%

Immune Modulatory Properties of Collagen in Cancer

2021

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“…This was accompanied by the destruction of stromal cells in PC, along with enhanced infiltration with anti-tumor immune cells [ 101 ]. Similar pre-clinical studies with S. typhimurium bioengineered to express collagenase and hyaluronidase demonstrated reduced collagen fibers in PC, resulting in a reduced tumor burden and proliferation [ 102 , 103 ]. Attenuated Listeria monocytogenes is another bacterium extensively studied in cancer therapy, due to its ability to efficiently activate TLR-mediated innate immune responses and antigen presentation, resulting in CD8+T-cell-mediated anti-tumor responses [ 104 , 105 , 106 ].…”

Section: Microbiome In Cancer Therapymentioning

confidence: 94%

Complex Role of Microbiome in Pancreatic Tumorigenesis: Potential Therapeutic Implications

Amara

Yang

Tiriveedhi

et al. 2022

Cells

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Pancreatic cancer (PC) is the fourth leading cause of cancer-related mortality with limited diagnostic and therapeutic options. Although immunotherapy has shown promise in the treatment of several cancers, its role in pancreatic cancer is rather limited. Several studies have focused on determining the role of the tumor microenvironment with cancer-cell-intrinsic events and tumor-infiltrating immune cellular properties. However, in the past decade, there has been emerging research aimed at delineating the role of the host microbiome, including the metabolites from microbes and host responses, on pancreatic tumorigenesis. Importantly, there is emerging evidence suggesting the beneficial role of a gut microbiome transplant to improve immunotherapeutic outcomes in cancer patients. In this review, we summarize the recent understanding of the role of the microbiome in pancreatic cancer progression, along with its clinical diagnostic and therapeutic implications.

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“…Collagenase treatment loosens the ECM, allows an improved drug penetration and delivery and provides an antitumor effect ( 425 – 427 ). Alternatives to achieve collagen degradation include activators of matrix metalloproteinases ( 428 , 429 ), engineered bacteria ( 430 ) and armed oncolytic virus expressing ECM components ( 431 – 434 ).…”

Section: Clinical Impactmentioning

confidence: 99%

Cancer immune exclusion: breaking the barricade for a successful immunotherapy

et al. 2023

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Immunotherapy has changed the course of cancer treatment. The initial steps were made through tumor-specific antibodies that guided the setup of an antitumor immune response. A new and successful generation of antibodies are designed to target immune checkpoint molecules aimed to reinvigorate the antitumor immune response. The cellular counterpart is the adoptive cell therapy, where specific immune cells are expanded or engineered to target cancer cells. In all cases, the key for achieving positive clinical resolutions rests upon the access of immune cells to the tumor. In this review, we focus on how the tumor microenvironment architecture, including stromal cells, immunosuppressive cells and extracellular matrix, protects tumor cells from an immune attack leading to immunotherapy resistance, and on the available strategies to tackle immune evasion.

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Collagenase-Expressing Salmonella Targets Major Collagens in Pancreatic Cancer Leading to Reductions in Immunosuppressive Subsets and Tumor Growth

Cited by 13 publications

References 70 publications

Immune Modulatory Properties of Collagen in Cancer

Immune Modulatory Properties of Collagen in Cancer

Complex Role of Microbiome in Pancreatic Tumorigenesis: Potential Therapeutic Implications

Cancer immune exclusion: breaking the barricade for a successful immunotherapy

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