Showing papers on "Cytotoxic T cell published in 2022"

Immunogenic cell stress and death

Abstract: Dying mammalian cells emit numerous signals that interact with the host to dictate the immunological correlates of cellular stress and death. In the absence of reactive antigenic determinants (which is generally the case for healthy cells), such signals may drive inflammation but cannot engage adaptive immunity. Conversely, when cells exhibit sufficient antigenicity, as in the case of infected or malignant cells, their death can culminate with adaptive immune responses that are executed by cytotoxic T lymphocytes and elicit immunological memory. Suggesting a key role for immunogenic cell death (ICD) in immunosurveillance, both pathogens and cancer cells evolved strategies to prevent the recognition of cell death as immunogenic. Intriguingly, normal cells succumbing to conditions that promote the formation of post-translational neoantigens (for example, oxidative stress) can also drive at least some degree of antigen-specific immunity, pointing to a novel implication of ICD in the etiology of non-infectious, non-malignant disorders linked to autoreactivity. Immunogenic cell death (ICD) is central to both homeostatic and pathophysiological events. Kroemer et al. review the mechanisms of ICD and its role in therapy and disease.

Decade-long leukaemia remissions with persistence of CD4+ CAR T cells

Abstract: The adoptive transfer of T lymphocytes reprogrammed to target tumour cells has demonstrated potential for treatment of various cancers1-7. However, little is known about the long-term potential and clonal stability of the infused cells. Here we studied long-lasting CD19-redirected chimeric antigen receptor (CAR) T cells in two patients with chronic lymphocytic leukaemia1-4 who achieved a complete remission in 2010. CAR T cells remained detectable more than ten years after infusion, with sustained remission in both patients. Notably, a highly activated CD4+ population emerged in both patients, dominating the CAR T cell population at the later time points. This transition was reflected in the stabilization of the clonal make-up of CAR T cells with a repertoire dominated by a small number of clones. Single-cell profiling demonstrated that these long-persisting CD4+ CAR T cells exhibited cytotoxic characteristics along with ongoing functional activation and proliferation. In addition, longitudinal profiling revealed a population of gamma delta CAR T cells that prominently expanded in one patient concomitant with CD8+ CAR T cells during the initial response phase. Our identification and characterization of these unexpected CAR T cell populations provide novel insight into the CAR T cell characteristics associated with anti-cancer response and long-term remission in leukaemia.

KIR+CD8+ T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19

Abstract: In this work, we find that CD8+ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49+CD8+ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8+ T cells efficiently eliminated pathogenic gliadin-specific CD4+ T cells from the leukocytes of celiac disease patients in vitro. We also find elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 patients, correlating with disease severity and vasculitis. Selective ablation of Ly49+CD8+ T cells in virus-infected mice led to autoimmunity after infection. Our results indicate that in both species, these regulatory CD8+ T cells act specifically to suppress pathogenic T cells in autoimmune and infectious diseases. Description Say a KIR-full goodbye to autoimmunity Ly49+CD8+ T cells are a subset of CD8+ T cells that show immunoregulatory activity in mice. Li et al. report the existence of a similar CD8+ T cell subset in humans that expresses killer cell immunoglobulin-like receptors (KIRs), a functional parallel of the mouse Ly49 family (see the Perspective by Levescot and Bensussan). These cells, which can suppress self-reactive CD4+ T cells, were more abundant in patients with autoimmune conditions such as celiac disease, multiple sclerosis, and lupus, as well as in patients infected with influenza virus or severe acute respiratory syndrome coronavirus 2. When mice selectively deficient in Ly49+CD8+ T cells were infected with viruses, they showed normal antiviral immune responses but eventually developed symptoms of autoimmune disease. KIR+CD8+ T cells may therefore be an important therapeutic target for the control of autoimmune diseases such as “long COVID” that emerge after viral infections. —STS Regulatory CD8+ T cells act to suppress pathogenic T cells in autoimmune and infectious diseases in mice and humans. INTRODUCTION Previous studies have identified Ly49+CD8+ T cells as a CD8+ T cell subset with regulatory functions in mice. These cells can suppress myelin oligodendrocyte glycoprotein (MOG)–specific pathogenic CD4+ T cells through their cytolytic activity and thereby ameliorate experimental autoimmune encephalomyelitis (EAE). However, whether a similar CD8+ regulatory T cell subset exists in humans and whether its suppressive activity extends beyond autoimmune diseases to play a more general role in peripheral tolerance remains to be determined. RATIONALE Because killer cell immunoglobulin-like receptors (KIRs) are the evolutionary counterpart of the mouse Ly49 family in humans, we investigated whether KIR+CD8+ T cells are the phenotypic and functional equivalent of mouse Ly49+CD8+ T cells. We assessed the frequency of KIR+CD8+ T cells in human autoimmune and infectious diseases and analyzed their transcriptional profiles as well as T cell receptor (TCR) repertoires. Moreover, we developed an in vitro functional assay to test their regulatory functions on gliadin-specific disease-driving CD4+ T cells from patients with celiac disease (CeD) and to study the mechanisms of suppression. To further elucidate their role in infectious diseases, we analyzed the effects of selective ablation of their murine counterpart on the antiviral responses during infection and tissue pathology after resolution of viral infection. RESULTS The frequency of KIR+CD8+ T cells was higher in the blood and inflamed tissues of patients with multiple autoimmune diseases compared with those of healthy controls. Furthermore, the increase of duodenal KIR+CD8+ T cells positively correlated with disease activity in CeD. In vitro, KIR+CD8+ T cells were able to specifically eliminate gliadin-specific pathogenic CD4+ T cells from the leukocytes of CeD patients through their cytotoxicity in a class I major histocompatibility complex (MHC)–dependent manner. Moreover, our RNA sequencing (RNA-seq) analysis revealed many similarities between human KIR+CD8+ T cells and mouse Ly49+CD8+ T cells, which suggests that KIR+CD8+ T cells are the functional and phenotypic equivalents of mouse Ly49+CD8+ T cells in humans. The expression of inhibitory KIR receptors appeared to suppress the activation and cytotoxic functions of KIR+CD8+ T cells. Moreover, elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells (Tregs), were also observed in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)– or influenza-infected patients and correlated with vasculitis in COVID-19 patients. Notably, expanded KIR+CD8+ T cells from healthy subjects and different diseases displayed shared phenotypes and similar TCR sequences as revealed by single-cell RNA-seq and TCR sequencing (TCR-seq). Finally, the selective depletion of Ly49+CD8+ T cells in virus-infected mice did not interfere with the antiviral responses but resulted in exacerbated autoimmunity after infection, demonstrating the critical role that this subset of CD8+ Tregs plays in controlling harmful self-reactivity in infectious diseases. CONCLUSION We identify KIR+CD8+ T cells as an important regulatory T cell subset in humans. They are induced as part of the response during an autoimmune reaction or infection and may act as a negative feedback mechanism to specifically suppress the self-reactive or otherwise pathogenic cells without affecting the immune responses against pathogens. This subset of CD8+ Tregs appears to play an important role in maintaining peripheral tolerance, which is distinct from and likely complementary to that of CD4+ Tregs. Our findings also provide insights into understanding the relationship between autoimmunity and infectious diseases and into the development of potential therapeutic approaches targeting KIR+CD8+ T cells to suppress undesirable self-reactivity in autoimmune disorders and infectious diseases. The proposed role of CD8+ regulatory T cells in peripheral tolerance. KIR+CD8+ T cells are the equivalent of mouse Ly49+CD8+ T cells in humans, with similar regulatory functions. During an infection, this kind of CD8+ regulatory T cell is induced and suppresses those CD4+ T cells with a strong reactivity to self, which may cause autoimmunity without interfering with the immune responses against pathogens.

Immunogenic Cell Death Activates the Tumor Immune Microenvironment to Boost the Immunotherapy Efficiency

Abstract: Tumor immunotherapy is only effective in a fraction of patients due to a low response rate and severe side effects, and these challenges of immunotherapy in clinics can be addressed through induction of immunogenic cell death (ICD). ICD is elicited from many antitumor therapies to release danger associated molecular patterns (DAMPs) and tumor‐associated antigens to facilitate maturation of dendritic cells (DCs) and infiltration of cytotoxic T lymphocytes (CTLs). The process can reverse the tumor immunosuppressive microenvironment to improve the sensitivity of immunotherapy. Nanostructure‐based drug delivery systems (NDDSs) are explored to induce ICD by incorporating therapeutic molecules for chemotherapy, photosensitizers (PSs) for photodynamic therapy (PDT), photothermal conversion agents for photothermal therapy (PTT), and radiosensitizers for radiotherapy (RT). These NDDSs can release loaded agents at a right dose in the right place at the right time, resulting in greater effectiveness and lower toxicity. Immunotherapeutic agents can also be combined with these NDDSs to achieve the synergic antitumor effect in a multi‐modality therapeutic approach. In this review, NDDSs are harnessed to load multiple agents to induce ICD by chemotherapy, PDT, PTT, and RT in combination of immunotherapy to promote the therapeutic effect and reduce side effects associated with cancer treatment.

A nanovaccine for antigen self-presentation and immunosuppression reversal as a personalized cancer immunotherapy strategy

Abstract: The strategy of combining a vaccine with immune checkpoint inhibitors has been widely investigated in cancer management, but the complete response rate for this strategy is still unresolved. We describe a genetically engineered cell membrane nanovesicle that integrates antigen self-presentation and immunosuppression reversal (ASPIRE) for cancer immunotherapy. The ASPIRE nanovaccine is derived from recombinant adenovirus-infected dendritic cells in which specific peptide-major histocompatibility complex class I (pMHC-I), anti-PD1 antibody and B7 co-stimulatory molecules are simultaneously anchored by a programmed process. ASPIRE can markedly improve antigen delivery to lymphoid organs and generate broad-spectrum T-cell responses that eliminate established tumours. This work presents a powerful vaccine formula that can directly activate both native T cells and exhausted T cells, and suggests a general strategy for personalized cancer immunotherapy. Cancer vaccines based on endogenous modified dendritic cells can activate cytotoxic T cells in an antigen-specific manner, but the short life of dendritic cells on injection in the body limits the efficacy of the strategies. Here the authors design biomimetic nanovesicles derived from antigen-presenting dendritic cell membranes for cancer vaccination and the simultaneous delivery of immune co-stimulatory molecules, showing robust antitumour activity in animal models.

Omicron-Specific Cytotoxic T-Cell Responses After a Third Dose of mRNA COVID-19 Vaccine Among Patients With Multiple Sclerosis Treated With Ocrelizumab.

Abstract: Importance The SARS-CoV-2 variant B.1.1.529 (Omicron) escapes neutralizing antibodies elicited after COVID-19 vaccination, while T-cell responses might be better conserved. It is crucial to assess how a third vaccination modifies these responses, particularly for immunocompromised patients with readily impaired antibody responses. Objective To determine T-cell responses to the Omicron spike protein in anti-CD20-treated patients with multiple sclerosis (MS) before and after a third messenger RNA COVID-19 vaccination. Design, Setting, and Participants In this prospective cohort study conducted from March 2021 to November 2021 at the University Hospital Geneva, adults with MS receiving anti-CD20 treatment (ocrelizumab) were identified by their treating neurologists and enrolled in the study. A total of 20 patients received their third dose of messenger RNA COVID-19 vaccine and were included in this analysis. Interventions Blood sampling before and 1 month after the third vaccine dose. Main Outcomes and Measures Quantification of CD4 and CD8 (cytotoxic) T cells specific for the SARS-CoV-2 spike proteins of the vaccine strain as well as the Delta and Omicron variants, comparing frequencies before and after the third vaccine dose. Results Of 20 included patients, 11 (55%) were male, and the median (IQR) age was 45.8 (37.8-53.3) years. Spike-specific CD4 and CD8 T-cell memory against all variants were maintained in 9 to 12 patients 6 months after their second vaccination, albeit at lower median frequencies against the Delta and Omicron variants compared with the vaccine strain (CD8 T cells: Delta, 83.0%; 95% CI, 73.6-114.5; Omicron, 78.9%; 95% CI, 59.4-100.0; CD4 T cells: Delta, 72.2%; 95% CI, 67.4-90.5; Omicron, 62.5%; 95% CI, 51.0-89.0). A third dose enhanced the number of responders to all variants (11 to 15 patients) and significantly increased CD8 T-cell responses, but the frequencies of Omicron-specific CD8 T cells remained 71.1% (95% CI, 41.6-96.2) of the responses specific to the vaccine strain. Conclusions and Relevance In this cohort study of patients with MS treated with ocrelizumab, there were robust T-cell responses recognizing spike proteins from the Delta and Omicron variants, suggesting that COVID-19 vaccination in patients taking B-cell-depleting drugs may protect them against serious complications from COVID-19 infection. T-cell response rates increased after the third dose, demonstrating the importance of a booster dose for this population.

PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program

Abstract: Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection1. Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1+TCF1+ stem-like CD8+ T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8+ T cells that resemble highly functional effector CD8+ T cells seen after an acute viral infection. The generation of these qualitatively superior CD8+ T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1+TCF1+ stem-like CD8+ T cells, also referred to as precursors of exhausted CD8+ T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8+ T cells emerging from the stem-like CD8+ T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25–CD122–CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer2,3, and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies. PD-1+TCF1+ stem-like CD8+ T cells—precursors of exhausted CD8+ T cells—are not fate-locked into the exhaustion program; their differentiation trajectory can be changed by IL-2 signals.

T cells specific for α-myosin drive immunotherapy-related myocarditis

Abstract: Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy1. The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1–/–Ctla4+/– mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration2. Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1–/–Ctla4+/– mice, we identify clonal effector CD8+ T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1–/–Ctla4+/– mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, which required CD8+ T cells. The cardiac-specific protein α-myosin, which is absent from the thymus3,4, was identified as the cognate antigen source for three major histocompatibility complex class I-restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-MC were expanded by α-myosin peptides. Moreover, these α-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that α-myosin may be a clinically important autoantigen in ICI-MC. These studies underscore the crucial role for cytotoxic CD8+ T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity. Cytotoxic CD8+ T cells specific for α-myosin are identified as pivotal players in myocarditis associated with immune checkpoint inhibitor anticancer therapies.

Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity

Abstract: Abstract Lactate is a key metabolite produced from glycolytic metabolism of glucose molecules, yet it also serves as a primary carbon fuel source for many cell types. In the tumor-immune microenvironment, effect of lactate on cancer and immune cells can be highly complex and hard to decipher, which is further confounded by acidic protons, a co-product of glycolysis. Here we show that lactate is able to increase stemness of CD8 + T cells and augments anti-tumor immunity. Subcutaneous administration of sodium lactate but not glucose to mice bearing transplanted MC38 tumors results in CD8 + T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis reveals increased proportion of stem-like TCF-1-expressing CD8 + T cells among intra-tumoral CD3 + cells, a phenotype validated by in vitro lactate treatment of T cells. Mechanistically, lactate inhibits histone deacetylase activity, which results in increased acetylation at H3K27 of the Tcf7 super enhancer locus, leading to increased Tcf7 gene expression. CD8 + T cells in vitro pre-treated with lactate efficiently inhibit tumor growth upon adoptive transfer to tumor-bearing mice. Our results provide evidence for an intrinsic role of lactate in anti-tumor immunity independent of the pH-dependent effect of lactic acid, and might advance cancer immune therapy.

Rapid manufacturing of non-activated potent CAR T cells

Abstract: Chimaeric antigen receptor (CAR) T cells can generate durable clinical responses in B-cell haematologic malignancies. The manufacturing of these T cells typically involves their activation, followed by viral transduction and expansion ex vivo for at least 6 days. However, the activation and expansion of CAR T cells leads to their progressive differentiation and the associated loss of anti-leukaemic activity. Here we show that functional CAR T cells can be generated within 24 hours from T cells derived from peripheral blood without the need for T-cell activation or ex vivo expansion, and that the efficiency of viral transduction in this process is substantially influenced by the formulation of the medium and the surface area-to-volume ratio of the culture vessel. In mouse xenograft models of human leukaemias, the rapidly generated non-activated CAR T cells exhibited higher anti-leukaemic in vivo activity per cell than the corresponding activated CAR T cells produced using the standard protocol. The rapid manufacturing of CAR T cells may reduce production costs and broaden their applicability. Potent chimaeric antigen receptor T cells can be generated within one day from T cells derived from peripheral blood without the need for T-cell activation.

Reversing T-cell Exhaustion in Cancer: Lessons Learned from PD-1/PD-L1 Immune Checkpoint Blockade

Abstract: Anti-PD-1/PD-L1 immune checkpoint blockade (ICB) therapy has revolutionized the treatment of many types of cancer over the past decade. The initial therapeutic hypothesis underlying the mechanism of anti-PD-1/PD-L1 ICB was built around the premise that it acts locally in the tumor, reversing the exhaustion of PD-1hiCD8+ T cells by "releasing the brakes." However, recent studies have provided unprecedented insight into the complexity within the CD8+ T-cell pool in the tumor microenvironment (TME). Single-cell RNA sequencing and epigenetic profiling studies have identified novel cell surface markers, revealing heterogeneity within CD8+ T-cell states classified as unique. Moreover, these studies highlighted that following ICB, CD8+ T-cell states within and outside the TME possess a differential capacity to respond, mobilize to the TME, and seed an effective antitumor immune response. In aggregate, these recent developments have led to a reevaluation of our understanding of both the underlying mechanisms and the sites of action of ICB therapy. Here, we discuss the evidence for the reversibility of CD8+ T-cell exhaustion after ICB treatment and its implication for the further development of cancer immunotherapy.

CD3+CD4-CD8- (Double-Negative) T Cells in Inflammation, Immune Disorders and Cancer

Abstract: The crucial role of CD4+ and CD8+ T cells in shaping and controlling immune responses during immune disease and cancer development has been well established and used to achieve marked clinical benefits. CD3+CD4-CD8- double-negative (DN) T cells, although constituting a rare subset of peripheral T cells, are gaining interest for their roles in inflammation, immune disease and cancer. Herein, we comprehensively review the origin, distribution and functions of this unique T cell subgroup. First, we focused on characterizing multifunctional DN T cells in various immune responses. DN regulatory T cells have the capacity to prevent graft-versus-host disease and have therapeutic value for autoimmune disease. T helper-like DN T cells protect against or promote inflammation and virus infection depending on the specific settings and promote certain autoimmune disease. Notably, we clarified the role of DN tumor-infiltrating lymphocytes and outlined the potential for malignant proliferation of DN T cells. Finally, we reviewed the recent advances in the applications of DN T cell-based therapy for cancer. In conclusion, a better understanding of the heterogeneity and functions of DN T cells may help to develop DN T cells as a potential therapeutic tool for inflammation, immune disorders and cancer.

Androgen conspires with the CD8 ⁺ T cell exhaustion program and contributes to sex bias in cancer

Abstract: Sex bias exists in the development and progression of nonreproductive organ cancers, but the underlying mechanisms are enigmatic. Studies so far have focused largely on sexual dimorphisms in cancer biology and socioeconomic factors. Here, we establish a role for CD8+ T cell-dependent antitumor immunity in mediating sex differences in tumor aggressiveness, which is driven by the gonadal androgen but not sex chromosomes. A male bias exists in the frequency of intratumoral antigen-experienced Tcf7/TCF1+ progenitor exhausted CD8+ T cells that are devoid of effector activity as a consequence of intrinsic androgen receptor (AR) function. Mechanistically, we identify a novel sex-specific regulon in progenitor exhausted CD8+ T cells and a pertinent contribution from AR as a direct transcriptional transactivator of Tcf7/TCF1. The T cell-intrinsic function of AR in promoting CD8+ T cell exhaustion in vivo was established using multiple approaches including loss-of-function studies with CD8-specific Ar knockout mice. Moreover, ablation of the androgen-AR axis rewires the tumor microenvironment to favor effector T cell differentiation and potentiates the efficacy of anti-PD-1 immune checkpoint blockade. Collectively, our findings highlight androgen-mediated promotion of CD8+ T cell dysfunction in cancer and imply broader opportunities for therapeutic development from understanding sex disparities in health and disease.

Expansion of cytotoxic tissue-resident CD8+ T cells and CCR6+CD161+ CD4+ T cells in the nasal mucosa following mRNA COVID-19 vaccination

Abstract: Abstract Vaccines against SARS-CoV-2 have shown high efficacy in clinical trials, yet a full immunologic characterization of these vaccines, particularly within the human upper respiratory tract, is less well known. Here, we enumerate and phenotype T cells in nasal mucosa and blood using flow cytometry before and after vaccination with the Pfizer-BioNTech COVID-19 vaccine ( n = 21). Tissue-resident memory (Trm) CD8 + T cells expressing CD69 + CD103 + increase in number ~12 days following the first and second doses, by 0.31 and 0.43 log 10 cells per swab respectively ( p = 0.058 and p = 0.009 in adjusted linear mixed models). CD69 + CD103 + CD8 + T cells in the blood decrease post-vaccination. Similar increases in nasal CD8 + CD69 + CD103 − T cells are observed, particularly following the second dose. CD4 + cells co-expressing CCR6 and CD161 are also increased in abundance following both doses. Stimulation of nasal CD8 + T cells with SARS-CoV-2 spike peptides elevates expression of CD107a at 2- and 6-months ( p = 0.0096) post second vaccine dose, with a subset of donors also expressing increased cytokines. These data suggest that nasal T cells may be induced and contribute to the protective immunity afforded by this vaccine.

PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells

Abstract: Abstract Expansion and differentiation of antigen-experienced PD-1 + TCF-1 + stem-like CD8 + T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade 1–4 . Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of ‘better effector’ CD8 + T cells similar to those generated in an acute infection 5 . IL-2 binding to the IL-2 receptor α-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor β- and γ-chain (IL-2Rβγ)-biased agonists are currently being developed 6–10 . Here we show that IL-2Rβγ-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2Rβγ on the same cell recovers the ability to differentiate stem-like CD8 + T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis -targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.

Landscape of helper and regulatory antitumour CD4+ T cells in melanoma

Abstract: Within the tumour microenvironment, CD4+ T cells can promote or suppress antitumour responses through the recognition of antigens presented by human leukocyte antigen (HLA) class II molecules1,2, but how cancers co-opt these physiologic processes to achieve immune evasion remains incompletely understood. Here we performed in-depth analysis of the phenotype and tumour specificity of CD4+ T cells infiltrating human melanoma specimens, finding that exhausted cytotoxic CD4+ T cells could be directly induced by melanoma cells through recognition of HLA class II-restricted neoantigens, and also HLA class I-restricted tumour-associated antigens. CD4+ T regulatory (TReg) cells could be indirectly elicited through presentation of tumour antigens via antigen-presenting cells. Notably, numerous tumour-reactive CD4+ TReg clones were stimulated directly by HLA class II-positive melanoma and demonstrated specificity for melanoma neoantigens. This phenomenon was observed in the presence of an extremely high tumour neoantigen load, which we confirmed to be associated with HLA class II positivity through the analysis of 116 melanoma specimens. Our data reveal the landscape of infiltrating CD4+ T cells in melanoma and point to the presentation of HLA class II-restricted neoantigens and direct engagement of immunosuppressive CD4+ TReg cells as a mechanism of immune evasion that is favoured in HLA class II-positive melanoma.

Allelic variation in class I HLA determines CD8+ T cell repertoire shape and cross-reactive memory responses to SARS-CoV-2.

Abstract: Effective presentation of antigens by human leukocyte antigen (HLA) class I molecules to CD8+ T cells is required for viral elimination and generation of long-term immunological memory. In this study, we applied a single-cell, multiomic technology to generate a unified ex vivo characterization of the CD8+ T cell response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) across four major HLA class I alleles. We found that HLA genotype conditions key features of epitope specificity, TCRα/β sequence diversity, and the utilization of pre-existing SARS-CoV-2-reactive memory T cell pools. Single-cell transcriptomics revealed functionally diverse T cell phenotypes of SARS-CoV-2-reactive T cells, associated with both disease stage and epitope specificity. Our results show that HLA variations notably influence the CD8+ T cell repertoire shape and utilization of immune recall upon SARS-CoV-2 infection.