🔬 Immunotherapy in Pseudomyxoma Peritonei (PMP): Can We Overcome the Mucin Barrier?

Immunotherapy in pseudomyxoma peritonei.

Study Title: Progress on immuno-microenvironment and immune-related therapies in patients with pseudomyxoma peritonei
Published In: Cancer Biology & Medicine, 2024
DOI: 10.20892/j.issn.2095-3941.2024.0109
Study Focus: Tumor immune microenvironment, adenosine signaling, and immunotherapeutic strategies in PMP

Introduction: immunotherapy in pseudomyxoma peritonei.

Pseudomyxoma peritonei (PMP) is a rare, indolent malignancy characterized by progressive accumulation of mucinous ascites due to peritoneal dissemination of mucin-producing neoplastic cells. While PMP is generally slow-growing, it can cause significant morbidity through progressive abdominal distention, bowel obstruction, and cachexia. Most cases originate from appendiceal neoplasms, although rarer origins include ovarian, urachal, or colonic sources. Despite aggressive surgical treatment with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), recurrence remains common, particularly in high-volume or incomplete resections.

This 2024 review by Zhao et al. in Cancer Biology & Medicine explores the biological and immunologic underpinnings of PMP, focusing on the tumor immune microenvironment (TIME), GNAS-driven mucin production, and emerging immune-targeted therapies.

GNAS Mutations and the Molecular Pathogenesis of PMP

Immunotherapy in pseudomyxoma peritonei

Genomic Landscape: GNAS mutations are present in approximately 50% of PMP cases, particularly at codon 201 (R201C and R201H). These hotspot mutations result in the loss of GTPase activity in the Gsα subunit, causing constitutive activation of adenylyl cyclase, increased cyclic AMP (cAMP) levels, and downstream activation of protein kinase A (PKA).

Impact on Mucin Regulation:

• GNAS-driven cAMP signaling activates transcription factors CREB and ATF, which in turn upregulate expression of MUC2 and MUC5AC, both key gel-forming mucins.
• MUC2 is consistently overexpressed in >99% of PMP cases.
• The mucin composition—particularly the MUC2:MUC5B:MUC5AC ratio—affects the rheologic and adhesive properties of the intraperitoneal mucin, contributing to progressive fibrotic encapsulation.

Pathophysiological Implications:

• The mucin-rich environment impairs immune cell mobility, oxygen diffusion, and drug penetration.
• GNAS mutations promote a phenotypic shift—not oncogenic transformation per se—but create a physical and chemical barrier that supports immune evasion and disease persistence.

Tumor Immune Microenvironment (TIME) in PMP

The TIME in PMP is profoundly immunosuppressive, with notable deficiencies in cytotoxic effector cell activity and dominance of immunoregulatory elements.

T Cell Dynamics:

• CD8+ T cells are sparse and functionally suppressed.
• CD4+ helper T cells dominate but are largely skewed toward regulatory phenotypes, promoting tolerance.

B Cells:

• CD20+ B lymphocytes are present but at low density and display limited clonal expansion.

Myeloid Cells and Neutrophils:

• Myeloid-derived suppressor cells (MDSCs): Marked by CD15+, these cells inhibit T cell activity via arginase and reactive oxygen species.
• Tumor-associated neutrophils (TANs): Frequently present and promote angiogenesis, tissue remodeling, and immune suppression.

Macrophage Polarization:

• M2-polarized macrophages (CD163+) are abundant.
• M2 macrophages secrete IL-10, TGF-β, and VEGF, reinforcing immune evasion and supporting stromal fibrosis.

Natural Killer (NK) Cell Dysfunction:

• CD56dim NK cells exhibit reduced expression of activating receptors (NKp30, NKp46, NKG2D).
• Their cytotoxicity is further dampened by hypoxia, mucin barriers, and altered stromal cytokine production.

Stromal Contribution:

• Activated fibroblasts express fibroblast-activating protein (FAP) and secrete FGF2, which modulates angiogenesis and ECM remodeling.

Cytokine and Chemokine Milieu:

• PMP ascites is rich in pro-inflammatory and immunosuppressive cytokines:
  • IL-6, IL-8, IP-10, MCP-1: Elevated over 200-fold compared to serum.
  • COX-2/PGE2 and TGF-β pathways drive immune tolerance and Treg induction.

Adenosinergic Axis in Immunosuppression:

• Overexpression of CD39 and CD73 (ectoenzymes) converts extracellular ATP to adenosine.
• Adenosine binds to A2AR on T cells, dendritic cells, and macrophages, promoting T cell anergy and IL-10 production.
• This pathway is independent of GNAS mutation, indicating it is a convergent mechanism in PMP immune evasion.

Immunotherapy in pseudomyxoma peritonei: Strategies

Immune Checkpoint Inhibitors (ICIs):

• PD-1 and CTLA-4 blockade is being tested in the DART S1609 basket trial for rare tumors, including PMP.
• PD-L1 is low or absent on PMP tumor cells but may be present on stromal immune cells.
• Efficacy likely limited without combination strategies that remodel the TIME.

OK-432 Immunostimulation:

• Derived from heat-killed Streptococcus pyogenes (picibanil), this agent enhances macrophage and dendritic cell activity.
• Used intraperitoneally or subcutaneously.
• Reports from China and Japan suggest prolonged progression-free intervals, though mechanistic data are limited.

Neoantigen Vaccines and Personalized Peptides:

• Mucin-derived peptides and Gsα R201H-based neoepitopes show promise in generating T cell responses.
• Requires further validation in patient-derived models and correlation with HLA typing.
• Combining vaccines with ICIs may amplify antitumor immune responses.

Radioimmunotherapy (RIT):

• Uses radiolabeled antibodies (e.g., 131I-B72.3) directed against TAG-72, a mucin-associated glycoprotein.
• Demonstrated selective peritoneal uptake and retention.
• Potential for early postoperative delivery akin to HIPEC to eliminate residual microscopic disease.

Combination Strategies:

• Mucolytics + Immunotherapy: Enzymes breaking down mucin (e.g., bromelain, N-acetylcysteine) could enhance immune penetration.
• Adenosine Axis Blockade: A2AR antagonists in combination with PD-1 blockade to overcome immune paralysis.
• Oncolytic viruses or TLR agonists to induce innate immunity in an otherwise “cold” TME.

Clinical Challenges and Future Directions

Research Gaps:

• Lack of stable PMP cell lines and mouse models limits preclinical testing.
• Minimal tumor mutational burden (TMB) and low neoantigen load reduce spontaneous immunogenicity.

Biomarker Development:

• Need for TIME stratification markers (e.g., A2AR, CD73 expression, TIL profiles).
• Use of multiplex IHC and spatial transcriptomics to better define immune niches.

Clinical Trials and Translation:

• Most immunotherapy applications are still in early-phase studies.
• Basket trials or multi-arm immunotherapy protocols should include PMP-specific arms with detailed correlative studies.

Conclusion

Pseudomyxoma peritonei presents a formidable therapeutic challenge due to its mucin-dominated biology and profoundly immunosuppressive microenvironment. GNAS mutations drive excessive mucin production via cAMP signaling, while the tumor milieu impairs immune activation at multiple levels. However, innovative immunotherapies—ranging from checkpoint blockade to mucin-targeted vaccines and adenosine pathway inhibitors—offer emerging hope. Future success will depend on deeper profiling of the TIME, biomarker-guided trial design, and thoughtful combinatorial strategies tailored to the unique immunobiology of PMP.

Paper Reference: Zhao Q, Wei T, Ma R, et al. Progress on immuno-microenvironment and immune-related therapies in patients with pseudomyxoma peritonei. Cancer Biol Med. 2024. doi:10.20892/j.issn.2095-3941.2024.0109

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