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T follicular helper cells (Tfh), a subset of [CD4.sup.+] T cells, provide requisite help to B cells in the germinal centers (GC) of lymphoid tissue. GC Tfh are identified by high expression of the chemokine receptor CXCR5 and the inhibitory molecule PD-1. Although more accessible, blood contains lower frequencies of [CXCR5.sup.+] and [PD-1.sup.+] cells that have been termed circulating Tfh (cTfh). However, it remains unclear whether GC Tfh exit lymphoid tissues and populate this cTfh pool. To examine exiting cells, we assessed the phenotype of Tfh present within the major conduit of efferent lymph from lymphoid tissues into blood, the human thoracic duct. Unlike what was found in blood, we consistently identified a CXCR5-bright PD-1-bright ([CXCR5.sup.Br][PD-1.sup.Br]) Tfh population in thoracic duct lymph (TDL). These [CXCR5.sup.Br][PD-1.sup.Br] TDL Tfh shared phenotypic and transcriptional similarities with GC Tfh. Moreover, components of the epigenetic profile of GC Tfh could be detected in [CXCR5.sup.Br][PD-1.sup.Br] TDL Tfh and the transcriptional imprint of this epigenetic signature was enriched in an activated cTfh subset known to contain vaccine-responding cells. Together with data showing shared TCR sequences between the [CXCR5.sup.Br][PD-1.sup.Br] TDL Tfh and cTfh, these studies identify a population in TDL as a circulatory intermediate connecting the biology of Tfh in blood to Tfh in lymphoid tissue., Introduction T follicular helper cells (Tfh) are a subset of [CD4.sup.+] T cells that provide B cell help within the follicles of secondary lymphoid tissues. Tfh promote B cell class [...]

Exhausted CD8.sup.+ T (T.sub.ex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (T.sub.eff) or memory (T.sub.mem) CD8.sup.+ T cells. T.sub.ex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T.sub.ex cells are a distinct immune subset, with a unique chromatin landscape compared with T.sub.eff and T.sub.mem cells. However, the mechanisms that govern the transcriptional and epigenetic development of T.sub.ex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of T.sub.ex cells in mice. TOX is largely dispensable for the formation of T.sub.eff and T.sub.mem cells, but it is critical for exhaustion: in the absence of TOX, T.sub.ex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in T.sub.ex cells. Robust expression of TOX therefore results in commitment to T.sub.ex cells by translating persistent stimulation into a distinct T.sub.ex cell transcriptional and epigenetic developmental program. The transcription factor TOX is a central regulator of the transcriptional and epigenetic development of exhausted T cells., Author(s): Omar Khan [sup.1] [sup.2] [sup.3] [sup.14] , Josephine R. Giles [sup.1] [sup.2] [sup.3] , Sierra McDonald [sup.4] [sup.5] [sup.6] , Sasikanth Manne [sup.1] [sup.2] , Shin Foong Ngiow [sup.1] [...]

Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and that this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8 of 27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks, with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pretreatment immune signature (neoadjuvant response signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade. Neoadjuvant PD-1 blockade in patients with resectable melanoma followed by adjuvant maintenance results in early immunological effects driving clinical benefit and reveals transcriptional and genomic mechanisms of response., Author(s): Alexander C. Huang [sup.1] [sup.2] [sup.3] [sup.4] , Robert J. Orlowski [sup.1] [sup.11] , Xiaowei Xu [sup.4] [sup.5] , Rosemarie Mick [sup.3] [sup.4] [sup.6] , Sangeeth M. George [sup.7] [...]

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (T[sub.ex] cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating T[sub.ex] cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade., Author(s): Alexander C. Huang (corresponding author) [1, 2, 3, 4]; Michael A. Postow [5, 6]; Robert J. Orlowski [1, 2, 3, 4]; Rosemarie Mick [3, 4, 7]; Bertram Bengsch [2, [...]