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In an era of rapid advances in immunotherapy for solid tumors, relatively little is known about the immune tumor microenvironment (iTME) of malignant pleural effusions (MPEs) and how to leverage the iTME for an overall antitumor effect. In this issue of the Journal, Wei and colleagues (pp. 174–184) report the results of a deeper investigation into the iTME of lung cancer MPE using a murine model (1). In particular, they focus on the role of a particular subpopulation of lymphocytes, termed gdT cells, a population that has not been well studied in the context of MPE. gdT cells have a unique T-cell receptor structure that is composed of two glycoprotein chains (one g chain and one d chain), in contrast to the more abundant and well-studied population of abT cells. There are two major subsets, distinguished by their Vd chain. Vd1 T cells are found in the thymus and periphery and react to a variety of stress-related antigens (e.g., heat shock proteins), whereas Vd2 T cells are the predominant subset in the blood (2). gdT cells have some key differences from abT cells that may translate to enhanced activity against infections and cancers: 1) they do not require antigen processing, 2) they can recognize antigen independently of major histocompatibility complex (MHC) peptide presentation, 3) they can recognize a broad range of antigens (most prominently lipid antigens), 4) they display attributes of both innate and adaptive immunity, 5) they can be activated rapidly (3), 6) their cytotoxicity is exerted through a variety of mechanisms (4), and 7) they can present antigen themselves, similarly to dendritic cells, and stimulate other immune cells (5). gdT cells have demonstrated antitumor activity in preclinical models of various solid cancers. They have also shown promise in a few clinical trials (6). Both gd1 and gd2 T cells are able to lyse tumor cells ex vivo (7, 8) and express chemokine receptors that augment tumor homing (9). A particular subset of gdT cells, Vg9Vd2T cells, have drawn interest for tumor immunotherapy applications (10). However, some studies have found circumstances in which gd T cells become exhausted (11), are suppressed through checkpoint molecules (12), or may even serve a protumor role. Some studies observed tumor progression when Vd1 T cells exceeded Vd2 T cells in number (normally, Vd2 T cells are more numerous than Vd1 T cells in the peripheral blood) (13, 14). In some reports, the presence of tumor-infiltrating gdT cells correlated with favorable outcomes in different cancers (15, 16), but in others the presence of gd T cells correlated with worse clinical outcomes (17). Some studies have shown that gd T cells can suppress other immune cells (18). IL-17A and IL-10 in the context of Vd T cells are of particular interest. IL-17 is traditionally known as a proinflammatory cytokine, but it has been reported to play both antiand protumor roles depending on the nature of the tumor microenvironment (19). Patients with lung cancer and lower levels of MPE IL-17 were found to have longer overall survival times (20). An increased frequency of IL-17 T cells was associated with prolonged survival of patients with lung cancer and MPE (21). IL-10, on the other hand, is traditionally known as an antiinflammatory cytokine and has been shown to promote MPE formation in mouse models (22). IL-10 has been reported to have an inverse relationship with IL-17 in MPEs (23). Only a few studies have examined the role of gd T cells specifically in MPEs. Investigators in China detected gd T cells in lung cancer MPEs, but these were on average lower in frequency than in matched peripheral blood samples (24). Other investigators studying breast cancer MPEs reported highly variable frequencies of gd T cells in their samples (25). Wei and colleagues attempted to elucidate the role of gd T cells in MPEs, particularly in the context of IL-17 secretion. Having previously shown IL-10’s suppression of antitumor responses in murine MPEs, they also investigated whether IL-17–producing gd T cells (gdT17 cells) were suppressed by IL-10 in MPEs. This study is really three ministudies in one. In their first study, the authors used a murine model of MPE. LLC or MC38 cancer cells were introduced intrapleurally into C57BL/6 wild-type (WT) mice or IL-10 knockout mice. About 2 weeks after injection, MPE, blood, and spleen samples were collected and analyzed via flow cytometry. In the second study, the authors took gd T cells purified from mouse spleens, differentiated them for 3 days in vitro, and analyzed proliferation and cytokine production phenotype by flow cytometry. In the third study, they focused on the effect of antibody-based depletion of gd T cells in the murine LLC MPE model. The authors’main conclusion is that IL-10 deficiency increases gd T cells in MPEs via enhanced proliferation, and promotes gd T-cell production of IL-17A via upregulation of a transcription factor, RORgt. Following are some of the key observations of their study: 1) The authors found an increased frequency of dT17 cells and greater amounts of IL-17A in MPEs, which were enhanced in IL-10 deficiency. The majority of MPE gd T cells had an activated, effector memory phenotype. Interestingly, IL-10 deficiency led to lower expression of FasL and NKG2D on gd T cells. 2) The mechanism of IL-10 deficiency leading to enhanced MPE gd T cells was due to enhanced proliferation, not enhanced trafficking. IL-10 deficiency further augmented proliferation. 3) The transcription factor RORgt (which is involved in the differentiation of T-helper cell type 17 [Th17] cells) was expressed at higher levels in IL-10 gd T cells than in their WT counterparts. Other transcription factors (Tbet and IRF4) showed decreased expression in IL-10 gd T cells. 4) Overall, IL-10 mice had smaller MPE volumes and survived longer with MPEs than WT mice. Antibody depletion of gd T cells decreased the survival time of IL-10 MPE mice, but