Immune responses and immunotherapeutic interventions in malignant pleural mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive, primary pleural malignancy with poor prognosis, hypothesized to originate from a chronic inflammatory state within the pleura. Similar to what has been observed in other solid tumors (melanoma, ovarian and colorectal cancer), clinical and pre-clinical MPM investigations have correlated anti-tumor immune responses with improved survival. As such, a better understanding of the complex MPM tumor microenvironment is imperative in strategizing successful immunotherapies. Herein, we review the immune responses vital to the development and progression of MPM, as well as assess the role of immunomodulatory therapies, highlighting recent pre-clinical and clinical immunotherapy investigations.

Fig. 1

When challenged with either long asbestos fibers (a) or long carbon nanotubes (b), macrophages fail to satisfactorily phagocytose the encountered particles, as the particles are longer than macrophages can accommodate. Repeated phagocytotic efforts by macrophages fail to clear the long fibers (“frustrated phagocytosis”), resulting in continued generation of reactive oxygen species and secretion of pro-inflammatory cytokines, leading to prolonged inflammation. (Reprinted by permission from Macmillan Publishers Ltd: Nature Nanotechnology, [17].)

Fig. 2

Immune interactions and immunomodulation in MPM. CD4⁺/CD8⁺ T cells and N1 neutrophils have anti-tumor associations while regulatory T cells (T_regs), N2 neutrophils, and M2 macrophages have pro-tumor associations. Immunomodulation is designed to potentiate the anti-tumor cells, and dendritic cell therapy, TLR agonist, and IFN-β increase CD8 response, while anti-CD40 antibody mimics CD4⁺ assistance; IL-2 and IL-12 increase CD4⁺ and CD8⁺ responses. Therapies can also impair the pro-tumor cells. TGF-β polarizes neutrophils and macrophages to pro-tumor N2 and M2 phenotypes, respectively, as well as promoting T_regs. TGF-β blockade results in increased N1 neutrophils and CD8⁺ cells. Anti-CD25 antibody and cyclophosphamide can deplete T_regs, while anti-CCL2/12 antibody may impair T_reg trafficking. In addition, therapies can target a specific tumor antigen—SS1P, MORAb-009, and mesothelin CAR target mesothelin, while WT-1 peptide vaccine augments the immune response against WT-1-expressing MPM