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Targeting MHC-E as a new strategy for vaccines and immunotherapeutics
MHC-E is a highly conserved, non-polymorphic MHC protein that engages inhibitory and activating receptors on natural killer (NK) cells and T cells and can also present antigens to T cell receptors. NK cell responses driven by activating receptor interactions with MHC-E are implicated in controlling chronic viral infections and cancer. Immunotherapeutic targeting of interactions between MHC-E and inhibitory receptors to increase the activation of NK cells and T cells shows promise in improving antitumour immune responses. Furthermore, MHC-E-restricted CD8+ T cells elicited by cytomegalovirus-based vaccines might, for certain infections and cancers, be more effective than CD8+ T cells restricted by classical MHC class I or class II molecules. The ability of MHC-E to regulate or mediate both innate and adaptive immune responses independently of an individual’s MHC haplotype raises the possibility of new, universally effective vaccines and immunotherapies for infectious disease and cancer. Although the therapeutic exploitation of MHCE is still in its infancy, recent advances in the understanding of MHC-E biology show enormous potential, as described in this Review.
Inclusion of cGAMP within virus-like particle vaccines enhances their immunogenicity.
Cyclic GMP-AMP (cGAMP) is an immunostimulatory molecule produced by cGAS that activates STING. cGAMP is an adjuvant when administered alongside antigens. cGAMP is also incorporated into enveloped virus particles during budding. Here, we investigate whether inclusion of cGAMP within viral vaccine vectors enhances their immunogenicity. We immunise mice with virus-like particles (VLPs) containing HIV-1 Gag and the vesicular stomatitis virus envelope glycoprotein G (VSV-G). cGAMP loading of VLPs augments CD4 and CD8 T-cell responses. It also increases VLP- and VSV-G-specific antibody titres in a STING-dependent manner and enhances virus neutralisation, accompanied by increased numbers of T follicular helper cells. Vaccination with cGAMP-loaded VLPs containing haemagglutinin induces high titres of influenza A virus neutralising antibodies and confers protection upon virus challenge. This requires cGAMP inclusion within VLPs and is achieved at markedly reduced cGAMP doses. Similarly, cGAMP loading of VLPs containing the SARS-CoV-2 Spike protein enhances Spike-specific antibody titres. cGAMP-loaded VLPs are thus an attractive platform for vaccination.
B cell profiles, antibody repertoire and reactivity reveal dysregulated responses with autoimmune features in melanoma
AbstractB cells are known to contribute to the anti-tumor immune response, especially in immunogenic tumors such as melanoma, yet humoral immunity has not been characterized in these cancers to detail. Here we show comprehensive phenotyping in samples of circulating and tumor-resident B cells as well as serum antibodies in melanoma patients. Memory B cells are enriched in tumors compared to blood in paired samples and feature distinct antibody repertoires, linked to specific isotypes. Tumor-associated B cells undergo clonal expansion, class switch recombination, somatic hypermutation and receptor revision. Compared with blood, tumor-associated B cells produce antibodies with proportionally higher levels of unproductive sequences and distinct complementarity determining region 3 properties. The observed features are signs of affinity maturation and polyreactivity and suggest an active and aberrant autoimmune-like reaction in the tumor microenvironment. Consistent with this, tumor-derived antibodies are polyreactive and characterized by autoantigen recognition. Serum antibodies show reactivity to antigens attributed to autoimmune diseases and cancer, and their levels are higher in patients with active disease compared to post-resection state. Our findings thus reveal B cell lineage dysregulation with distinct antibody repertoire and specificity, alongside clonally-expanded tumor-infiltrating B cells with autoimmune-like features, shaping the humoral immune response in melanoma.
Innate stimulation of B cells ex vivo enhances antibody secretion and identifies tumour-reactive antibodies from cancer patients
Abstract Human B cells and their expressed antibodies are crucial in conferring immune protection. Identifying pathogen-specific antibodies following infection is possible due to enhanced humoral immunity against well-described molecules on the pathogen surface. However, screening for cancer-reactive antibodies remains challenging since target antigens are often not identified a priori and the frequency of circulating B cells recognizing cancer cells is likely very low. We investigated whether combined ex vivo culture of human B cells with three innate stimuli, interleukin-17 (IL-17), B-cell activation factor (BAFF), and the toll-like receptor 9 (TLR-9) agonist DNA motif CpG ODN 2006 (CpG), each known to activate B cells through different signalling pathways, promote cell activation, proliferation, and antibody production. Combined IL-17+BAFF+CpG prolonged B-cell survival and increased proliferation compared with single stimuli. IL-17+BAFF+CpG triggered higher IgG secretion, likely by activating differentiated, memory and class-switched CD19+CD20+CD27+IgD- B cells. Regardless of anti-FOLR antibody seropositive status, IL-17+BAFF+CpG combined with a monovalent tumour-associated antigen (folate receptor alpha [FOLR]) led to secreted antibodies recognizing the antigen and the antigen-expressing IGROV1 cancer cells. In a seropositive individual, FOLR stimulation favoured class-switched memory B-cell precursors (CD27-CD38-IgD-), class-switched memory B cells and anti-FOLR antibody production, while IL-17+BAFF+CpG combined with FOLR, promoted class-switched memory B-cell precursors and antibody-secreting (CD138+IgD-) plasma cells. Furthermore, IL-17+BAFF+CpG stimulation of peripheral blood B cells from patients with melanoma revealed tumour cell-reactive antibodies in culture supernatants. These findings suggest that innate signals stimulate B-cell survival and antibody production and may help identify low-frequency antigen-reactive humoral responses.
Tumor-Infiltrating B Lymphocyte Profiling Identifies IgG-Biased, Clonally Expanded Prognostic Phenotypes in Triple-Negative Breast Cancer
AbstractIn breast cancer, humoral immune responses may contribute to clinical outcomes, especially in more immunogenic subtypes. Here, we investigated B lymphocyte subsets, immunoglobulin expression, and clonal features in breast tumors, focusing on aggressive triple-negative breast cancers (TNBC). In samples from patients with TNBC and healthy volunteers, circulating and tumor-infiltrating B lymphocytes (TIL-B) were evaluated. CD20+CD27+IgD− isotype-switched B lymphocytes were increased in tumors, compared with matched blood. TIL-B frequently formed stromal clusters with T lymphocytes and engaged in bidirectional functional cross-talk, consistent with gene signatures associated with lymphoid assembly, costimulation, cytokine–cytokine receptor interactions, cytotoxic T-cell activation, and T-cell–dependent B-cell activation. TIL-B–upregulated B-cell receptor (BCR) pathway molecules FOS and JUN, germinal center chemokine regulator RGS1, activation marker CD69, and TNFα signal transduction via NFκB, suggesting BCR–immune complex formation. Expression of genes associated with B lymphocyte recruitment and lymphoid assembly, including CXCL13, CXCR4, and DC-LAMP, was elevated in TNBC compared with other subtypes and normal breast. TIL-B–rich tumors showed expansion of IgG but not IgA isotypes, and IgG isotype switching positively associated with survival outcomes in TNBC. Clonal expansion was biased toward IgG, showing expansive clonal families with specific variable region gene combinations and narrow repertoires. Stronger positive selection pressure was present in the complementarity determining regions of IgG compared with their clonally related IgA in tumor samples. Overall, class-switched B lymphocyte lineage traits were conspicuous in TNBC, associated with improved clinical outcomes, and conferred IgG-biased, clonally expanded, and likely antigen-driven humoral responses.Significance:Tumor-infiltrating B lymphocytes assemble in clusters, undergoing B-cell receptor–driven activation, proliferation, and isotype switching. Clonally expanded, IgG isotype-biased humoral immunity associates with favorable prognosis primarily in triple-negative breast cancers.
Antiviral antibody responses to systemic administration of an oncolytic RNA virus: the impact of standard concomitant anticancer chemotherapies
BackgroundOncolytic reovirus therapy for cancer induces a typical antiviral response to this RNA virus, including neutralizing antibodies. Concomitant treatment with cytotoxic chemotherapies has been hypothesized to improve the therapeutic potential of the virus. Chemotherapy side effects can include immunosuppression, which may slow the rate of the antiviral antibody response, as well as potentially make the patient more vulnerable to viral infection.MethodReovirus neutralizing antibody data were aggregated from separate phase I clinical trials of reovirus administered as a single agent or in combination with gemcitabine, docetaxel, carboplatin and paclitaxel doublet or cyclophosphamide. In addition, the kinetics of individual antibody isotypes were profiled in sera collected in these trials.ResultsThese data demonstrate preserved antiviral antibody responses, with only moderately reduced kinetics with some drugs, most notably gemcitabine. All patients ultimately produced an effective neutralizing antibody response.ConclusionPatients’ responses to infection by reovirus are largely unaffected by the concomitant drug treatments tested, providing confidence that RNA viral treatment or infection is compatible with standard of care treatments.
Combined anti‐PD‐1 and anti‐CTLA‐4 checkpoint blockade: Treatment of melanoma and immune mechanisms of action
AbstractCytotoxic T‐lymphocyte associated protein‐4 (CTLA‐4) and the Programmed Death Receptor 1 (PD‐1) are immune checkpoint molecules that are well‐established targets of antibody immunotherapies for the management of malignant melanoma. The monoclonal antibodies, Ipilimumab, Pembrolizumab, and Nivolumab, designed to interfere with T cell inhibitory signals to activate immune responses against tumors, were originally approved as monotherapy. Treatment with a combination of immune checkpoint inhibitors may improve outcomes compared to monotherapy in certain patient groups and these clinical benefits may be derived from unique immune mechanisms of action. However, treatment with checkpoint inhibitor combinations also present significant clinical challenges and increased rates of immune‐related adverse events. In this review, we discuss the potential mechanisms attributed to single and combined checkpoint inhibitor immunotherapies and clinical experience with their use.
B Cells in Patients With Melanoma: Implications for Treatment With Checkpoint Inhibitor Antibodies
The contributions of the humoral immune response to melanoma are now widely recognized, with reports of positive prognostic value ascribed to tumor-infiltrating B cells (TIL-B) and increasing evidence of B cells as key predictors of patient response to treatment. There are disparate views as to the pro- and anti-tumor roles of B cells. B cells appear to play an integral role in forming tumor-associated tertiary lymphoid structures (TLSs) which can further modulate T cell activation. Expressed antibodies may distinctly influence tumor regulation in the tumor microenvironment, with some isotypes associated with strong anti-tumor immune response and others with progressive disease. Recently, B cells have been evaluated in the context of cancer immunotherapy. Checkpoint inhibitors (CPIs), targeting T cell effector functions, have revolutionized the management of melanoma for many patients; however, there remains a need to accurately predict treatment responders. Increasing evidence suggests that B cells may not be simple bystanders to CPI immunotherapy. Mature and differentiated B cell phenotypes are key positive correlates of CPI response. Recent evidence also points to an enrichment in activatory B cell phenotypes, and the contribution of B cells to TLS formation may facilitate induction of T cell phenotypes required for response to CPI. Contrastingly, specific B cell subsets often correlate with immune-related adverse events (irAEs) in CPI. With increased appreciation of the multifaceted role of B cell immunity, novel therapeutic strategies and biomarkers can be explored and translated into the clinic to optimize CPI immunotherapy in melanoma.
Adsorption of antigen to polymeric nanoparticles enhances cytotoxic T-cell responses and anti-tumor immunity by targeting conventional type 1 dendritic cells.
Tumor rejection is primarily mediated by cytotoxic T cells, making them critical targets for therapeutic cancer vaccines. Vaccine adjuvants can modulate innate immunity, influencing adaptive immune responses. For particulate adjuvants, such as polymeric nanoparticles, physicochemical properties-including size, charge, composition and antigen location within the formulation-can shape these responses. Free-soluble antigens typically fail to induce sufficient dendritic cell maturation and cross-presentation needed for robust CD8+ T-cell activation. However, this can be enhanced by delivering antigen with nanoparticles of appropriate size. While adjuvants like oil-in-water emulsions do not require antigen association for vaccine efficacy, the importance of antigen location in the adjuvanticity of polymeric nanoparticles is less clear. We demonstrate that colocalization of antigen and polymeric nanoparticles through antigen adsorption enhances proliferation and activation of antigen-specific CD8+ T cells following intramuscular vaccination. While type 1 conventional dendritic cells (cDC1) can prime CD8+ T cells in other settings, their requirement with polymeric nanoparticles has not been fully addressed. We show that nanoparticle-induced CD8+ T-cell responses rely on cDC1s. The therapeutic efficacy of a polymeric nanoparticle vaccine was significantly enhanced when antigen was adsorbed on nanoparticles, leading to reduced tumor growth and prolonged survival in mice challenged with immunologically hot (MC38) and cold (B16F10) tumors expressing ovalbumin. Furthermore, vaccination with nanoparticle-adsorbed antigen synergized with anti-PD-1 checkpoint blockade, enhancing protection, especially against B16F10-ovalbumin tumors. This work highlights the role of antigen association with polymeric nanoparticles in eliciting CD8+ T-cell responses for the development of effective therapeutic cancer vaccines.
Rational design of polymer‐based particulate vaccine adjuvants
AbstractVaccination is considered one of the major milestones in modern medicine, facilitating the control and eradication of life‐threatening infectious diseases. Vaccine adjuvants are a key component of many vaccines, serving to steer antigen‐specific immune responses and increase their magnitude. Despite major advances in the field of adjuvant research over recent decades, our understanding of their mechanism of action remains incomplete. This hinders our capacity to further improve these adjuvant technologies, so addressing how adjuvants induce and control the induction of innate and adaptive immunity is a priority. Investigating how adjuvant physicochemical properties, such as size and charge, exert immunomodulatory effects can provide valuable insights and serve as the foundation for the rational design of vaccine adjuvants. Most clinically applied adjuvants are particulate in nature and polymeric particulate adjuvants present advantages due to stability, biocompatibility profiles, and flexibility in terms of formulation. These properties can impact on antigen release kinetics and biodistribution, cellular uptake and targeting, and drainage to the lymphatics, consequently dictating the induction of innate, cellular, and humoral adaptive immunity. A current focus is to apply rational design principles to the development of adjuvants capable of eliciting robust cellular immune responses including CD8+ cytotoxic T‐cell and Th1‐biased CD4+ T‐cell responses, which are required for vaccines against intracellular pathogens and cancer. This review highlights recent advances in our understanding of how particulate adjuvants, especially polymer‐based particulates, modulate immune responses and how this can be used as a guide for improved adjuvant design.
[Bladder cancer immunological background and biomarkers.].
Bladder cancer was one of the first to have a successful treatment based on immune system stimulation, recognized by patient survival and tumor recurrence data. In addition, bladder tumors are now known to have high antigenic load and are therefore considered to be susceptible to respond well to new immunotherapies. For these reasons, studying the mechanism of action of bladder cancer immunological-based treatments can provide valuable information both to improve their current use and to under stand why they work in some patients while others do not tolerate this therapy or have tumor progression. In this article, we will focus on the immune response generated by treatment of non-muscle invasive bladder tumors with BCG, as well as the relationship between this knowledge and new immunotherapies. We will first describe the main activities of the immune system, to continue with the treatment of bladder cancer with BCG, its mechanism of action and biomarkers. Finally, we will summarize the observations that led to the useof monoclonal antibody immunotherapy in cancer and will describe some of the new immunotherapies in use to treat bladder cancer patients.
PD-1 suppresses the maintenance of cell couples between cytotoxic T cells and target tumor cells within the tumor.
The killing of tumor cells by CD8+ T cells is suppressed by the tumor microenvironment, and increased expression of inhibitory receptors, including programmed cell death protein-1 (PD-1), is associated with tumor-mediated suppression of T cells. To find cellular defects triggered by tumor exposure and associated PD-1 signaling, we established an ex vivo imaging approach to investigate the response of antigen-specific, activated effector CD8+ tumor-infiltrating lymphocytes (TILs) after interaction with target tumor cells. Although TIL-tumor cell couples readily formed, couple stability deteriorated within minutes. This was associated with impaired F-actin clearing from the center of the cellular interface, reduced Ca2+ signaling, increased TIL locomotion, and impaired tumor cell killing. The interaction of CD8+ T lymphocytes with tumor cell spheroids in vitro induced a similar phenotype, supporting a critical role of direct T cell-tumor cell contact. Diminished engagement of PD-1 within the tumor, but not acute ex vivo blockade, partially restored cell couple maintenance and killing. PD-1 thus contributes to the suppression of TIL function by inducing a state of impaired subcellular organization.
Association of PD-1, LAG-3 and TIM-3 expression on intratumoral CD8 T-cells with response to atezolizumab in a Real-World-Evidence biomarker study for advanced urothelial carcinoma patients.
Blockade of the PD-1/PD-L1 pathway is part of the standard treatment for advanced urothelial cancer, but reliable predictive biomarkers have not been identified. Here, we analyze with Multiplexed Quantitative Immunofluorescence the pretreatment tumor microenvironment (TME) of urothelial cancer samples from patients treated with atezolizumab to identify correlations with treatment efficacy in a Real-World-Evidence (RWE) study. We assessed with Multiplexed Quantitative Immunofluorescence the expression of CD8, PD-1, TIM-3 and LAG-3 on T-cells in the different compartments of the TME (tumor, stroma and whole tissue) in pre-treatment tissue microarrays. We studied associations between the expression of the markers and clinical efficacy. One hundred-nine patients received atezolizumab, showing an overall response rate of 23.8%. Safety was comparable to previous studies with atezolizumab. Pre-treatment tumor samples were available from 45 patients. CD8+ T-cell density was significantly increased in the tumor compartment, but not in the stromal compartment, of patients experiencing complete and partial responses, as compared with patients presenting stable disease or progression. Similar results were observed for co-expression of CD8/PD-1, CD8/TIM-3 and CD8/PD-1/TIM-3/LAG-3. Our findings support the relevance of the density and spatial distribution of CD8+ T-cells and its co-receptors for the clinical efficacy of single-agent PD-L1 blockade in patients with advanced urothelial cancer. RWE studies are a valuable tool for identifying predictive biomarkers.