Why Immunotherapy Works Differently in Peritoneal Mesothelioma

The Location Problem

Immune checkpoint therapy has changed how pleural mesothelioma is treated. The combination of Opdivo and Yervoy extended survival in a landmark Phase 3 trial. Durvalumab combined with chemotherapy showed similar promise.

But nearly every major immunotherapy trial has excluded patients with peritoneal mesothelioma. The assumption was that pleural results could be extrapolated. A new study in Scientific Reports (Nature) suggests that assumption may be wrong.

Researchers at the Harry Perkins Institute of Medical Research in Australia found that where mesothelioma grows in the body fundamentally changes how the immune system interacts with it. The same cancer cells, implanted in different anatomical locations, created entirely different immune environments and responded differently to checkpoint therapy.

What the Study Found

The research team implanted identical mesothelioma cell lines in three locations in mice: the pleural cavity (chest lining), the peritoneal cavity (abdominal lining), and subcutaneously (under the skin). They then compared the tumor microenvironment and treatment response across all three.

The differences were striking.

Pleural tumors developed an inflammatory microenvironment with strong interferon signaling, higher T cell and NK cell infiltration, and gene signatures associated with immunotherapy response. Peritoneal tumors developed the opposite: an immune-suppressive environment with low interferon and TNF-alpha signaling, fewer T cells and NK cells, and dominance by macrophages. The gene expression profile matched signatures previously linked to checkpoint therapy resistance. Subcutaneous tumors showed the strongest inflammatory signature of all three, but they grow differently from tumors in their natural anatomical sites and are considered less clinically relevant.

When the team treated the tumors with immune checkpoint therapy, the results followed the pattern predicted by the microenvironment data. Checkpoint therapy significantly delayed tumor growth in subcutaneous models. But the same treatment, against the same cell line, was ineffective when tumors grew in the peritoneal cavity.

Why the Peritoneum Is Different

The study’s transcriptomic analysis revealed that peritoneal tumors activate cell proliferation pathways (MYC, E2F, G2M) that have been linked to immunotherapy resistance. At the same time, the inflammatory pathways that checkpoint drugs rely on, including interferon alpha, interferon gamma, IL-6 STAT3, and IL-2 STAT5 signaling, were significantly less active.

The immune cells that did infiltrate peritoneal tumors were dominated by macrophages with low expression of MHC-II, a marker associated with antigen presentation. In other words, the immune cells present in peritoneal tumors appeared less capable of recognizing and attacking cancer cells.

Pleural tumors, by contrast, showed more lymphoid aggregates, higher T cell and NK cell percentages, and stronger engagement of the inflammatory pathways that make checkpoint therapy work.

The researchers confirmed these findings were not specific to one cell line or mouse strain. The same location-dependent patterns appeared across two different mesothelioma cell lines in two different mouse strains.

What This Means for Peritoneal Patients

The implications are significant for the roughly 9% to 24% of people with mesothelioma whose disease originates in the peritoneum.

Peritoneal mesothelioma actually has a better overall prognosis than pleural, with median survival of 33 months compared to 13 months, largely due to the effectiveness of cytoreductive surgery combined with heated intraperitoneal chemotherapy (HIPEC). But for patients whose disease cannot be surgically removed, treatment options are limited.

The study’s authors suggest that sensitizing the peritoneal microenvironment to immunotherapy may require combination strategies. Possibilities include therapies targeting macrophages or B cells (such as anti-CD40 antibodies), myeloid reprogramming approaches, or dual-mechanism drugs that attack tumors through both immune and non-immune pathways.

This may help explain early clinical observations. A retrospective study of 24 people with peritoneal mesothelioma treated with pembrolizumab found only a 21% partial response rate, considerably lower than rates seen in pleural trials. Case reports have described individual peritoneal patients responding well to checkpoint therapy, but prospective controlled data remain scarce.

Limitations

This is a preclinical study using mouse models, and its findings cannot be directly applied to human treatment decisions. The researchers used sarcomatoid-type mesothelioma cell lines (epithelioid syngeneic models are limited in mice), and implanted tumors may not fully replicate the complexity of naturally occurring human mesothelioma.

The team also noted that tumors were compared at the same time point rather than the same size, meaning some microenvironment differences could reflect tumor bulk rather than location alone.

A Phase 2 clinical trial (NCT05041062) is currently investigating perioperative ipilimumab plus nivolumab in resected peritoneal mesothelioma, which may provide some of the first controlled human data on checkpoint therapy in this population.