Treatment of malignant pleural effusions: the case for localized immunotherapy

Abstract

Malignant pleural effusions (MPE) are a common terminal pathway for many cancers, with an estimated United States incidence of more than 150,000 cases per year. MPE is an aggressive disease with a uniformly fatal prognosis and a life expectancy of only 3 to 12 months. The development of an effective targeted therapy represents a pressing unmet need. This commentary focuses on how cellular and humoral components condition the pleural space as a tumor-promoting, wound-healing environment. Despite an abundance of potential antigen presenting and effector cells in the pleura, their physical isolation by the mesothelial barrier, the concentration of cytokines and chemokines driving the epithelial to mesenchymal transition (EMT) and M2 /Th-2 polarization, suppress tumor-specific immune effector responses. We argue that local immune repolarization must precede either immune checkpoint or cellular therapy to successfully eradicate pleural tumor. We further hypothesize that, because of its cellular content, a repolarized pleural space will provide an effective immune environment for generation of systemic anti-tumor response.

Keywords: Immunotherapy; Malignant pleural effusion; Pleural infiltrating T cells (PIT); Tumor associated macrophages (TAM).

Fig. 1

The interactions of tumor, TAM, and T-cells are highly dependent on the local immune environment. Tumors can evade an immune response, even when all of the required components are abundant and in close proximity. Panel a: Tumor effects on TAM. Tumor, particularly tumor that has undergone EMT, amplifies and maintains TAM M2-like wound healing polarization. TAM are recruited with tumor-secreted G-CSF and polarized through CD200/CD200R and CD90/CD11b interactions and tumor secreted IL-6 and IL-8. Panels b and c: Tumor and TAM polarization effects on T cells. M2 TAM polarization favors T-cell suppression through cytokines and programmed death ligand-induced apoptosis (b). The pleural space is isolated from the systemic circulation, permitting the maintenance of very high local cytokine and chemokine levels. The encircled space (Panel c) represents the isolated pleural immune environment in which potential effector cells are potently suppressed. It should be possible to repolarize the pleural immune environment with local delivery of cytokines, activation signals, antibody-based therapeutics and ex vivo activated PIT, tipping the balance in favor of the immune system. Panel d: Local repolarizing therapy results in M1 TAM polarization, providing presentation of tumor neo-antigens and costimulatory signals, culminating in the generation of tumor-specific effector T cells. Panel e: Once the immune blockade has been breached, antigen presenting cells and T cells can traffic to the draining lymph nodes where responding T cells can proliferate and differentiate. Once this has occurred, tumor specific T cells can be expected to home to other sites of metastasis