Dataset Information

Prognostic Role of Tumor Immune Microenvironment in Pleural Epithelioid Mesothelioma.

ABSTRACT:

Background

Pleural mesothelioma (MPM) is an aggressive malignancy with an average patient survival of only 10 months. Interestingly, about 5%-10% of the patients survive remarkably longer. Prior studies have suggested that the tumor immune microenvironment (TIME) has potential prognostic value in MPM. We hypothesized that high-resolution single-cell spatial profiling of the TIME would make it possible to identify subpopulations of patients with long survival and identify immunophenotypes for the development of novel treatment strategies.

Methods

We used multiplexed fluorescence immunohistochemistry (mfIHC) and cell-based image analysis to define spatial TIME immunophenotypes in 69 patients with epithelioid MPM (20 patients surviving ≥ 36 months). Five mfIHC panels (altogether 21 antibodies) were used to classify tumor-associated stromal cells and different immune cell populations. Prognostic associations were evaluated using univariate and multivariable Cox regression, as well as combination risk models with area under receiver operating characteristic curve (AUROC) analyses.

Results

We observed that type M2 pro-tumorigenic macrophages (CD163⁺pSTAT1^-HLA-DRA1^-) were independently associated with shorter survival, whereas granzyme B⁺ cells and CD11c⁺ cells were independently associated with longer survival. CD11c⁺ cells were the only immunophenotype increasing the AUROC (from 0.67 to 0.84) when added to clinical factors (age, gender, clinical stage, and grade).

Conclusion

High-resolution, deep profiling of TIME in MPM defined subgroups associated with both poor (M2 macrophages) and favorable (granzyme B/CD11c positivity) patient survival. CD11c positivity stood out as the most potential prognostic cell subtype adding prediction power to the clinical factors. These findings help to understand the critical determinants of TIME for risk and therapeutic stratification purposes in MPM.

SUBMITTER: Ollila H

PROVIDER: S-EPMC9251441 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Malignant pleural mesothelioma (MPM) is a rare and fatal disease of the pleural lining. Up to 80% of the MPM cases are linked to asbestos exposure. Even though its use has been banned in the industrialized countries, the cases continue to increase. MPM is a lethal cancer, with very little survival improvements in the last years, mirroring very limited therapeutic advances. Platinum-based chemotherapy in combination with pemetrexed and surgery are the standard of care, but prognosis is still unacceptably poor with median overall survival of approximately 12 months. The genomic landscape of MPM has been widely characterized showing a low mutational burden and the impairment of tumor suppressor genes. Among them, BAP1 and BLM are present as a germline inactivation in a small subset of patients and increases predisposition to tumorigenesis. Other studies have demonstrated a high frequency of mutations in DNA repair genes. Many therapy approaches targeting these alterations have emerged and are under evaluation in the clinic. High-throughput technologies have allowed the detection of more complex molecular events, like chromotripsis and revealed different transcriptional programs for each histological subtype. Transcriptional analysis has also paved the way to the study of tumor-infiltrating cells, thus shedding lights on the crosstalk between tumor cells and the microenvironment. The tumor microenvironment of MPM is indeed crucial for the pathogenesis and outcome of this disease; it is characterized by an inflammatory response to asbestos exposure, involving a variety of chemokines and suppressive immune cells such as M2-like macrophages and regulatory T cells. Another important feature of MPM is the dysregulation of microRNA expression, being frequently linked to cancer development and drug resistance. This review will give a detailed overview of all the above mentioned features of MPM in order to improve the understanding of this disease and the development of new therapeutic strategies.

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