Abstract
While T cell-based cancer immunotherapies have shown great promise, there remains a need to understand how individual metastatic tumor environments impart local T cell dysfunction. At advanced stages, cancers that metastasize to the pleural space can result in a malignant pleural effusion (MPE) that harbors abundant tumor and immune cells, often exceeding 108 leukocytes per liter. Unlike other metastatic sites, MPEs are readily and repeatedly accessible via indwelling catheters, providing an opportunity to study the interface between tumor dynamics and immunity. In the current study, we examined CD8+ T cells within MPEs collected from patients with heterogeneous primary tumors and at various stages in treatment to determine (1) if these cells possess anti-tumor activity following removal from the MPE, (2) factors in the MPE that may contribute to their dysfunction, and (3) the phenotypic changes in T cell populations that occur following ex vivo expansion. Co-cultures of CD8+ T cells with autologous CD45― tumor containing cells demonstrated cytotoxicity (p = 0.030) and IFNγ production (p = 0.003) that inversely correlated with percent of myeloid derived suppressor cells, lactate, and lactate dehydrogenase (LDH) within the MPE. Ex vivo expansion of CD8+ T cells resulted in progressive differentiation marked by distinct populations expressing decreased CD45RA, CCR7, CD127, and increased inhibitory receptors. These findings suggest that MPEs may be a source of tumor-reactive T cells and that the cellular and acellular components suppress optimal function.
Highlights
Facilitating endogenous anti-tumor activity in tumor-specific T cells is the cornerstone of multiple immunotherapy strategies to combat cancer
Malignant pleural effusions have a high prevalence of tumor associated immune cells that are readily and repeatedly accessible
While Malignant pleural effusions (MPE) present a clinical problem, they represent an opportunity to capture a broader and more reactive repertoire of T cells that are evolving against mutationally-driven neoepitope expressing tumor cells
Summary
Facilitating endogenous anti-tumor activity in tumor-specific T cells is the cornerstone of multiple immunotherapy strategies to combat cancer. Studies of the microenvironment within solid tumors have implicated hypoxia [1,2], nutrient availability [3,4,5], suppressive cytokines [6,7], other molecules (e.g., lactate dehydrogenase (LDH) or lactate) [8,9], and immunosuppressive cell subsets such as regulatory T cells (Tregs), tumor-associated macrophages (TAMs), and myeloid derived suppressor cells (MDSCs) [10,11,12,13]. Malignant pleural effusions (MPE) occur when tumor cells have metastasized to the pleura, resulting in the unopposed collection of fluid in the thoracic cavity, and are a common occurrence in many end stage epithelial cancers. At about 2500 cases per year in the United States, mesothelioma represents a very small burden of pleural disease when compared with over 150,000 annual MPEs in patients with advanced epithelial cancers
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
