Explore the vast range of titles available.

Characterization of the T cell response in individuals who recover from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is critical to understanding its contribution to protective immunity. A multiplexed peptide-MHC tetramer approach was used to screen 408 SARS-CoV-2 candidate epitopes for CD8+ T cell recognition in a cross-sectional sample of 30 coronavirus disease 2019 convalescent individuals. T cells were evaluated using a 28-marker phenotypic panel, and findings were modelled against time from diagnosis and from humoral and inflammatory responses. There were 132 SARS-CoV-2-specific CD8+ T cell responses detected across 6 different HLAs, corresponding to 52 unique epitope reactivities. CD8+ T cell responses were detected in almost all convalescent individuals and were directed against several structural and nonstructural target epitopes from the entire SARS-CoV-2 proteome. A unique phenotype for SARS-CoV-2-specific T cells was observed that was distinct from other common virus-specific T cells detected in the same cross-sectional sample and characterized by early differentiation kinetics. Modelling demonstrated a coordinated and dynamic immune response characterized by a decrease in inflammation, increase in neutralizing antibody titer, and differentiation of a specific CD8+ T cell response. Overall, T cells exhibited distinct differentiation into stem cell and transitional memory states (subsets), which may be key to developing durable protection.

Combination antiretroviral therapy (ART) is highly effective in controlling human immunodeficiency virus (HIV)-1 but requires lifelong medication due to the existence of a latent viral reservoir 1 , 2 . Potent broadly neutralizing antibodies (bNAbs) represent a potential alternative or adjuvant to ART. In addition to suppressing viremia, bNAbs may have T cell immunomodulatory effects as seen for other forms of immunotherapy 3 . However, this has not been established in individuals who are infected with HIV-1. Here, we document increased HIV-1 Gag-specific CD8 + T cell responses in the peripheral blood of all nine study participants who were infected with HIV-1 with suppressed blood viremia, while receiving bNAb therapy during ART interruption 4 . Increased CD4 + T cell responses were detected in eight individuals. The increased T cell responses were due both to newly detectable reactivity to HIV-1 Gag epitopes and the expansion of pre-existing measurable responses. These data demonstrate that bNAb therapy during ART interruption is associated with enhanced HIV-1-specific T cell responses. Whether these augmented T cell responses can contribute to bNAb-mediated viral control remains to be determined. T cell responses specific for HIV-1 Gag peptides increased in HIV-positive recipients of two broadly neutralizing antibodies with prolonged suppression of blood viremia during antiretroviral treatment interruption.

Chronic infection with lymphocytic choriomeningitis virus promotes the establishment of a population of stem-like PD-1 + CD8 + T cells that reside in lymphoid tissues and preferentially expand when the PD-1 inhibitory pathway is blocked. CD8 + T cells controlling chronic viral infections The long-term persistence of viral antigens drives the functional exhaustion of effector CD8 + T cells, yet the exhausted cells can still achieve a level of pathogen control during a chronic viral infection. Two groups reporting in this issue of Nature examine the mechanisms underlying the antiviral role of these immune cells. In a study of a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection and human HIV patients, Lilin Ye and colleagues report a population of partially exhausted CXCR5 + CD8 + T cells that is induced by chronic virus infection, resides in B-cell follicles, and controls viral replication. Differentiation and effector function of virus-specific CXCR5 + CD8 + T cells is regulated by the Id2–E2A signalling axis. Anti-PD-L1 antibody treatment is shown to inhibit viral replication in mice synergistically with adoptively transferred CXCR5 + CD8 + T cells. Rafi Ahmed and colleagues show that chronic LCMV infection in mice promotes a population of virus-specific CD8 + T cells with a T follicular helper (T FH )-like signature. These T cells expressed the PD-1 inhibitory receptor but also expressed co-stimulatory molecules and had a gene signature that was related to CD8 + T-cell memory precursor cells and hematopoietic stem cells. These findings provide a better understanding of T-cell exhaustion and have implications towards optimizing PD-1-directed immunotherapy. Chronic viral infections are characterized by a state of CD8 + T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor 1 , 2 , 3 , 4 . A better understanding of the mechanisms that regulate CD8 + T-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8 + T cells. Here we identify a population of virus-specific CD8 + T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These LCMV-specific CD8 + T cells expressed the PD-1 inhibitory receptor, but also expressed several costimulatory molecules such as ICOS and CD28. This CD8 + T-cell subset was characterized by a unique gene signature that was related to that of CD4 + T follicular helper (T FH ) cells, CD8 + T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4 + T H 1 cells and CD8 + terminal effectors. This CD8 + T-cell population was found only in lymphoid tissues and resided predominantly in the T-cell zones along with naive CD8 + T cells. These PD-1 + CD8 + T cells resembled stem cells during chronic LCMV infection, undergoing self-renewal and also differentiating into the terminally exhausted CD8 + T cells that were present in both lymphoid and non-lymphoid tissues. The proliferative burst after PD-1 blockade came almost exclusively from this CD8 + T-cell subset. Notably, the transcription factor TCF1 had a cell-intrinsic and essential role in the generation of this CD8 + T-cell subset. These findings provide a better understanding of T-cell exhaustion and have implications in the optimization of PD-1-directed immunotherapy in chronic infections and cancer.

Interleukin-1β (IL-1β) is abundant in the tumor microenvironment, where this cytokine can promote tumor growth, but also antitumor activities. We studied IL-1β during early tumor progression using a model of orthotopically introduced 4T1 breast cancer cells. Whereas there is tumor progression and spontaneous metastasis in wild-type (WT) mice, in IL-1β–deficient mice, tumors begin to grow but subsequently regress. This change is due to recruitment and differentiation of inflammatory monocytes in the tumor microenvironment. In WT mice, macrophages heavily infiltrate tumors, but in IL-1β–deficient mice, low levels of the chemokine CCL2 hamper recruitment of monocytes and, together with low levels of colony-stimulating factor-1 (CSF-1), inhibit their differentiation into macrophages. The low levels of macrophages in IL-1β–deficient mice result in a relatively high percentage of CD11b⁺ dendritic cells (DCs) in the tumors. In WT mice, IL-10 secretion from macrophages is dominant and induces immunosuppression and tumor progression; in contrast, in IL-1β–deficient mice, IL-12 secretion by CD11b⁺ DCs prevails and supports antitumor immunity. The antitumor immunity in IL-1β–deficient mice includes activated CD8⁺ lymphocytes expressing IFN-γ, TNF-α, and granzyme B; these cells infiltrate tumors and induce regression. WT mice with 4T1 tumors were treated with either anti–IL-1β or anti–PD-1 Abs, each of which resulted in partial growth inhibition. However, treating mice first with anti–IL-1β Abs followed by anti–PD-1 Abs completely abrogated tumor progression. These data define microenvironmental IL-1β as a master cytokine in tumor progression. In addition to reducing tumor progression, blocking IL-1β facilitates checkpoint inhibition.

Effective targeting of somatic cancer mutations to enhance the efficacy of cancer immunotherapy requires an individualized approach. Autogene cevumeran is a uridine messenger RNA lipoplex-based individualized neoantigen-specific immunotherapy designed from tumor-specific somatic mutation data obtained from tumor tissue of each individual patient to stimulate T cell responses against up to 20 neoantigens. This ongoing phase 1 study evaluated autogene cevumeran as monotherapy ( n  = 30) and in combination with atezolizumab ( n  = 183) in pretreated patients with advanced solid tumors. The primary objective was safety and tolerability; exploratory objectives included evaluation of pharmacokinetics, pharmacodynamics, preliminary antitumor activity and immunogenicity. Non-prespecified interim analysis showed that autogene cevumeran was well tolerated and elicited poly-epitopic neoantigen-specific responses, encompassing CD4 + and/or CD8 + T cells, in 71% of patients, most of them undetectable at baseline. Responses were detectable up to 23 months after treatment initiation. CD8 + T cells specific for several neoantigens constituted a median of 7.3% of circulating CD8 + T cells, reaching up to 23% in some patients. Autogene cevumeran-induced T cells were found within tumor lesions constituting up to 7.2% of tumor-infiltrating T cells. Clinical activity was observed, including one objective response in monotherapy dose escalation and in two patients with disease characteristics unfavorable for response to immunotherapy treated in combination with atezolizumab. These findings support the continued development of autogene cevumeran in earlier treatment lines. ClinicalTrials.gov registration: NCT03289962 . In this phase 1 trial, patients with locally advanced or metastatic solid tumors were treated with the individualized mRNA neoantigen-specific immunotherapy (iNeST) autogene cevumeran alone or in combination with the anti-PD-L1 agent atezolizumab, showing long-lasting neoantigen-specific immune responses and preliminary clinical activity, supporting further development of this therapeutic approach.

Anti-tumour immune activation by checkpoint inhibitors leads to durable responses in a variety of cancers, but combination approaches are required to extend this benefit beyond a subset of patients. In preclinical models tumour-derived VEGF limits immune cell activity while anti-VEGF augments intra-tumoral T-cell infiltration, potentially through vascular normalization and endothelial cell activation. This study investigates how VEGF blockade with bevacizumab could potentiate PD-L1 checkpoint inhibition with atezolizumab in mRCC. Tissue collections are before treatment, after bevacizumab and after the addition of atezolizumab. We discover that intra-tumoral CD8 + T cells increase following combination treatment. A related increase is found in intra-tumoral MHC-I, Th1 and T-effector markers, and chemokines, most notably CX3CL1 (fractalkine). We also discover that the fractalkine receptor increases on peripheral CD8 + T cells with treatment. Furthermore, trafficking lymphocyte increases are observed in tumors following bevacizumab and combination treatment. These data suggest that the anti-VEGF and anti-PD-L1 combination improves antigen-specific T-cell migration. Cancer immunotherapy can be used in combination with other therapies for a better response. Here, the authors conduct a phase Ib clinical study and report the clinical activity and the immune response of the anti-PDL1 agent, atezolizumab, in combination with bevacizumab in ten patients with metastatic renal cell carcinoma.

In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684. Autologous tumor lysate (ATL) dendritic cell (DC) vaccination can induce local and systemic anti-tumor immune responses in malignant glioma patients. In this randomized phase II clinical trial, the authors evaluate the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to ATL-DC vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas.

Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states 1 – 6 . Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox -deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1 , Entpd1 , Havcr2 , Cd244 and Tigit ), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, ‘non-exhausted’ immunophenotype, Tox -deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox -deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox -deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer. The nuclear factor TOX is highly expressed in antigen-specific dysfunctional T cells in tumours and exhausted T cells during chronic viral infection and is a crucial regulator of the differentiation of tumour-specific T cells.

The T cell infiltrates that are formed in human cancers are a modifier of natural disease progression and also determine the probability of clinical response to cancer immunotherapies. Recent technological advances that allow the single-cell analysis of phenotypic and transcriptional states have revealed a vast heterogeneity of intratumoural T cell states, both within and between patients, and the observation of this heterogeneity makes it critical to understand the relationship between individual T cell states and therapy response. This Review covers our current knowledge of the T cell states that are present in human tumours and the role that different T cell populations have been hypothesized to play within the tumour microenvironment, with a particular focus on CD8+ T cells. The three key models that are discussed herein are as follows: (1) the dysfunction of T cells in human cancer is associated with a change in T cell functionality rather than inactivity; (2) antigen recognition in the tumour microenvironment is an important driver of T cell dysfunctionality and the presence of dysfunctional T cells can hence be used as a proxy for the presence of a tumour-reactive T cell compartment; (3) a less dysfunctional population of tumour-reactive T cells may be required to drive a durable response to T cell immune checkpoint blockade.Recent single-cell RNA-sequencing studies have revealed a range of intratumoural T cell states, both within and between patients. This Review outlines the CD8+ T cell states that have been identified in human tumours and the potential roles they play in tumour control as well as how they are influenced by immune checkpoint blockade.

T cells are important in tumour immunity but a better understanding is needed of the differentiation of antigen-specific T cells in human cancer 1 , 2 . Here we studied CD8 T cells in patients with human papillomavirus (HPV)-positive head and neck cancer and identified several epitopes derived from HPV E2, E5 and E6 proteins that allowed us to analyse virus-specific CD8 T cells using major histocompatibility complex (MHC) class I tetramers. HPV-specific CD8 T cells expressed PD-1 and were detectable in the tumour at levels that ranged from 0.1% to 10% of tumour-infiltrating CD8 T lymphocytes (TILs) for a given epitope. Single-cell RNA-sequencing analyses of tetramer-sorted HPV-specific PD-1 + CD8 TILs revealed three transcriptionally distinct subsets. One subset expressed TCF7 and other genes associated with PD-1 + stem-like CD8 T cells that are critical for maintaining T cell responses in conditions of antigen persistence. The second subset expressed more effector molecules, representing a transitory cell population, and the third subset was characterized by a terminally differentiated gene signature. T cell receptor clonotypes were shared between the three subsets and pseudotime analysis suggested a hypothetical differentiation trajectory from stem-like to transitory to terminally differentiated cells. More notably, HPV-specific PD-1 + TCF-1 + stem-like TILs proliferated and differentiated into more effector-like cells after in vitro stimulation with the cognate HPV peptide, whereas the more terminally differentiated cells did not proliferate. The presence of functional HPV-specific PD-1 + TCF-1 + CD45RO + stem-like CD8 T cells with proliferative capacity shows that the cellular machinery to respond to PD-1 blockade exists in HPV-positive head and neck cancer, supporting the further investigation of PD-1 targeted therapies in this malignancy. Furthermore, HPV therapeutic vaccination efforts have focused on E6 and E7 proteins; our results suggest that E2 and E5 should also be considered for inclusion as vaccine antigens to elicit tumour-reactive CD8 T cell responses of maximal breadth. An analysis of human papillomavirus (HPV)-specific CD8 T cells in patients with head and neck cancer identifies functional PD-1 + TCF-1 + CD8 T cells in the tumour with implications for therapeutic vaccination and PD-1 directed immunotherapy.