Efficient Antigen Presentation Research Articles

Delivery of mRNA vaccine with a lipid-like material potentiates antitumor efficacy through Toll-like receptor 4 signaling

Intracellular delivery of messenger RNA (mRNA)-based cancer vaccine has shown great potential to elicit antitumor immunity. To achieve robust antitumor efficacy, mRNA encoding tumor antigens needs to be efficiently delivered and translated in dendritic cells with concurrent innate immune stimulation to promote antigen presentation. Here, by screening a group of cationic lipid-like materials, we developed a minimalist nanovaccine with C1 lipid nanoparticle (LNP) that could efficiently deliver mRNA in antigen presenting cells with simultaneous Toll-like receptor 4 (TLR4) activation and induced robust T cell activation. The C1 nanovaccine entered cells via phagocytosis and showed efficient mRNA-encoded antigen expression and presentation. Furthermore, the C1 lipid nanoparticle itself induced the expression of inflammatory cytokines such as IL-12 via stimulating TLR4 signal pathway in dendritic cells. Importantly, the C1 mRNA nanovaccine exhibited significant antitumor efficacy in both tumor prevention and therapeutic vaccine settings. Overall, our work presents a C1 LNP-based mRNA cancer nanovaccine with efficient antigen expression as well as self-adjuvant property, which may provide a platform for developing cancer immunotherapy for a wide range of tumor types.

The Role of Antigen Processing and Presentation in Cancer and the Efficacy of Immune Checkpoint Inhibitor Immunotherapy.

Simple SummaryA new class of drugs, termed Immune Checkpoint Inhibitors, has revolutionized cancer therapy during the last few years. Unfortunately, these drugs are only effective for a subset of patients and cancer types. Recent work has suggested that how well cancer cells present some of their molecules to the immune system is critical for patient responses to immunotherapy with immune checkpoint inhibitors. Here, we review the role of the biochemical pathway of antigen presentation in cancer and discuss how it can be modulated to enhance the efficacy of cancer immunotherapy.Recent clinical successes of cancer immunotherapy using immune checkpoint inhibitors (ICIs) are rapidly changing the landscape of cancer treatment. Regardless of initial impressive clinical results though, the therapeutic benefit of ICIs appears to be limited to a subset of patients and tumor types. Recent analyses have revealed that the potency of ICI therapies depends on the efficient presentation of tumor-specific antigens by cancer cells and professional antigen presenting cells. Here, we review current knowledge on the role of antigen presentation in cancer. We focus on intracellular antigen processing and presentation by Major Histocompatibility class I (MHCI) molecules and how it can affect cancer immune evasion. Finally, we discuss the pharmacological tractability of manipulating intracellular antigen processing as a complementary approach to enhance tumor immunogenicity and the effectiveness of ICI immunotherapy.

Strategies for Cancer Immunotherapy Using Induced Pluripotency Stem Cells-Based Vaccines.

Simple SummaryEffective cancer immunotherapies, with the objective to boost tumor-specific immune responses, is a game-changer in personalized cancer treatment. In immunotherapy, the immune system is exploited to recognize and destroy cancer cells, and this is only possible if a full recapitulation of tumor specific antigens complexity is achieved. Patient-derived induced pluripotent stem cells (iPSCs) share several characteristics with cancer (stem) cells (CSCs). The exploitation of iPSCs as a source of tumor- and patient-specific antigens guiding the immune system against cancer has been addressed recently in mice. Here, we will debate novel findings on the potential implication of cellular reprogramming and iPSCs plasticity for the design of novel cancer immunotherapeutic strategies.Despite improvements in cancer therapy, metastatic solid tumors remain largely incurable. Immunotherapy has emerged as a pioneering and promising approach for cancer therapy and management, and in particular intended for advanced tumors unresponsive to current therapeutics. In cancer immunotherapy, components of the immune system are exploited to eliminate cancer cells and treat patients. The recent clinical successes of immune checkpoint blockade and chimeric antigen receptor T cell therapies represent a turning point in cancer treatment. Despite their potential success, current approaches depend on efficient tumor antigen presentation which are often inaccessible, and most tumors turn refractory to current immunotherapy. Patient-derived induced pluripotent stem cells (iPSCs) have been shown to share several characteristics with cancer (stem) cells (CSCs), eliciting a specific anti-tumoral response when injected in rodent cancer models. Indeed, artificial cellular reprogramming has been widely compared to the biogenesis of CSCs. Here, we will discuss the state-of-the-art on the potential implication of cellular reprogramming and iPSCs for the design of patient-specific immunotherapeutic strategies, debating the similarities between iPSCs and cancer cells and introducing potential strategies that could enhance the efficiency and therapeutic potential of iPSCs-based cancer vaccines.

Recurrent bladder cancer in aging societies: Importance of major histocompatibility complex class I antigen presentation.

Aging is associated with an insufficient immune response that may lead to the initiation and progression of various malignancies. Bladder cancer (BC), prevalent in elderly patients, predominantly presents as recurrent nonmuscle invasive BC that requires further treatment. There is much interest in the activation of patients' immune cells with the focus on CD8+ T cells. Successful therapy should also ensure the efficient presentation of BC antigens by major histocompatibility complex (MHC) class I molecules. The purpose of this systematic review is to present the existing literature on the role of MHC class I in BC research and therapy. The bibliographic databases PubMed and Web of Science were searched for articles published between January 2009 and September 2020 that addressed MHC class I relationship to BC. We searched for available relevant publications on MHC class I and its role and regulation in BC, aging and MHC class I importance in BC immunotherapy. Based on the provided evidence, we propose that the loss of MHC class I expression in BC may lead to its recurrence after the transurethral resection and unresponsiveness to Bacillus Calmette-Guerin immunotherapy. We discuss different ways to enhance MHC class I antigen presentation to CD8+ T cells in BC treatment. The immune status characterized by MHC class I expression patterns and cancer-infiltrating immune cells may provide valuable prognostic information about which patients may benefit from transurethral resection of BC and additional immunotherapy.

Abstract CT237: A phase I study to assess the safety, tolerability, and immunogenicity of personalized neoantigen/cancer testis antigen nanovaccine (PVAC) for high-risk resected gastric cancer

Abstract Background: 35% of stage IIIB/C Gastric cancer patients will recurrent after D2 gastrectomy within one year. Mutation-derived epitopes (neoantigens) has been demonstrated to induce tumor cell specific immune responses controlling the tumor growth. Nanovaccine can increase antigen presentation efficiency and elicit potent antitumor T cell responses with robust therapeutic efficacy. We hypothesized that vaccination with neoantigens/cancer testis (CT) antigens could expand pre-existing and induce antigen-specific T-cells populations, favouring of tumor control enhancement. Here, we report the first-in-human application of this concept in gastric cancer. Methods: Patient-specific mutation-containing neoantigens were selected on the basis of tumour-specific mutations whole-exome sequencing (WES) and RNA sequencing. Cancer testis antigens were obtained according to immunohistochemical staining and HLA-binding affinity prediction. PVAC is an amphiphiles nanovaccine loaded with multiple personalized neoantigens/cancer testis antigens designed to induce antigen specific T cells and associated antitumor responses. PVAC will be administrated to stage IIIB/IIIC gastric carcinoma after six cycles of adjuvant chemotherapy (S-1/Oxaliplatin or S-1/docetaxel). Each patient received PVAC by subcutaneous injection on Days 1, 4, 8, 15, 22, 43, 64, 85, 169, administrated with the adjuvant montanide ISA 51 VG. Safety, immunogenicity and clinical efficacy will be evaluated. Results: 25 stage IIIB or IIIC gastric cancer patients were enrolled in this study. Mean age was 54.3 years old (range: 34-70), and ECOG performance scores were 0 or 1. Repeated dosing has been well tolerated with mild local discomfort and no DLTs. 10 of the 25 patients developed grade 1 local skin reactions with redness, swelling or subcutaneous indurations in the injection sites. Three patients were observed grade 2 local skin reactions in the injection sites. Four had grade 1 to 2 fever. No SAEs related to PVAC have been observed. Among median follow up time of 11.6 months (range: 7.5-24.0 months), only one patient had local recurrence at 10.5 months after surgery. The rest 24 patients remain disease free on study. Neoantigen specific T cell responses have been detected by IFN-γ Elispot from PBMCs. Conclusions: PVAC is a multiple neoantigens/CT antigens nanovaccine that personalizes tumor specific antigens and the individual patient's capacity to respond. Addition of PVAC may prolong progression-free survival (PFS) after the standard of care chemotherapy. Clinical trial information: ChiCTR1800017319. Citation Format: Qin Liu, Hanqing Qian, Jie Shao, Qiuping Xu, Huizi Sha, Yang Yang, Weifeng Wang, Lixia Yu, Baorui Liu, Jia Wei. A phase I study to assess the safety, tolerability, and immunogenicity of personalized neoantigen/cancer testis antigen nanovaccine (PVAC) for high-risk resected gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT237.

Galectin-8 Enhances T cell Response by Promotion of Antigen Internalization and Processing.

SummaryGalectin-8 (Gal-8) is a mammalian lectin endowed with immunostimulatory ability. In the present work, we demonstrate that Gal-8-glycan interactions on the surface of antigen-presenting cells (APCs) promote antigen binding and internalization, independently from antigen nature. Both Gal-8 and antigen were together internalized and localized in early endosomes. Interestingly, antigen processing by APCs was also accelerated in the presence of Gal-8 as a separate mechanism, distinct from the increased antigen internalization. Moreover, APCs pulsed together with antigen and Gal-8 were able to activate cognate CD4+ T cells more efficiently than those pulsed with antigen alone. This enhanced antigen presentation was still evident in the absence of costimulatory signals and APCs-derived soluble mediators. Therefore, our results provide evidence for as yet unrecognized mechanism by which Gal-8 stimulates the elicitation of the immune response in a lectin-dependent manner, by inducing antigen uptake and processing upon lattice formation at APCs surface.

O-antigen-deficient, live, attenuated Salmonella typhimurium confers efficient uptake, reduced cytotoxicity, and rapid clearance in chicken macrophages and lymphoid organs and induces significantly high protective immune responses that protect chickens against Salmonella infection

In the present study, we developed an O-antigen-deficient, live, attenuated Salmonella Typhimurium (ST) strain (JOL2377) and assessed its safety, macrophage toxicity, invasion into lymphoid tissues, immunogenicity, and protection against Salmonella infection in chickens. The JOL2377 induced significantly lower cytotoxicity and higher level of cytokine response in IL-2, IL-10, IL-4, and IFN- γ than the WT strain upon macrophage uptake. It did not persist in macrophages or in chicken organs and rapidly cleared without systemic infection. None of the chicken were found to secrete Salmonella in feces into the environment exacerbating its attenuation. Interestingly JOL2377 successfully arrived in immunological hot-spots such as spleen, liver and bursa of Fabricius for an efficient antigen presentation and immune stimulation. Mucosal and parenteral immunization with JOL2377 significantly elicit antigen-specific humoral (IgY) and cell mediated responses marked by peripheral blood mononuclear cell proliferation, cytokine induction, increase in T-cell responses than non-immunized control. JOL2377 did not generate significant levels of LPS specific antibodies as compared to the WT strain due to the lack of immunogenic O-antigen component from its LPS structure. Upon virulent challenge, route dependent efficacy differences were leaving the intramuscular route is superior to the oral route on reducing splenic and liver colonization of the challenge ST. The least cytotoxicity, virulence, and superior immunogenicity of JL2377 that effectively engage both humoral and IFN- γ mediated CMI responses present an ideal scenario in host immune modulation to fight against intracellular pathogen Salmonella.

Personalized neoantigen/cancer testis antigen nanovaccine (PVAC) mobilize specific therapeutic immunity for high-risk resected gastric cancer.

4535 Background: 35% of stage IIIB/C Gastric cancer patients will recurrent after D2 gastrectomy within one year. Mutation-derived epitopes (neoantigens) has been demonstrated to induce tumor cell specific immune responses controlling the tumor growth. Nanovaccine can increase antigen presentation efficiency and elicit potent antitumor T cell responses with robust therapeutic efficacy. We hypothesized that vaccination with neoantigens/cancer testis (CT) antigens could expand pre-existing and induce antigen-specific T-cells populations, favouring of tumor control enhancement. Here, we report the first-in-human application of this concept in gastric cancer. Methods: Patient-specific mutation-containing neoantigens were selected on the basis of tumour-specific mutations whole-exome sequencing (WES) and RNA sequencing. Cancer testis antigens were obtained according to immunohistochemical staining and HLA-binding affinity prediction. PVAC is an amphiphiles nanovaccine loaded with multiple personalized neoantigens/cancer testis antigens designed to induce antigen specific T cells and associated antitumor responses. PVAC will be administrated to stage IIIB/IIIC gastric carcinoma after six cycles of adjuvant chemotherapy (S-1/Oxaliplatin or S-1/docetaxel). Each patient received PVAC by subcutaneous injection on Days 1, 4, 8, 15, 22, 43, 64, 85, 169, administrated with the adjuvant montanide ISA 51 VG. Safety, immunogenicity and clinical efficacy will be evaluated. Results: 25 stage IIIB or IIIC gastric cancer patients were enrolled in this study. Mean age was 54.3 years old (range: 34-70), and ECOG performance scores were 0 or 1. Repeated dosing has been well tolerated with mild local discomfort and no DLTs. Three patients were observed grade 2 local skin reactions in the injection sites. No SAEs related to PVAC have been observed. Among median follow up time of 12.6 months (range: 8.5-25.0 months), only two patients had local recurrence at 24.0 months and 10.5 months after surgery, respectivelt. The rest 23 patients remain disease free on study. Neoantigen specific T cell responses have been detected by IFN-γ Elispot from PBMCs. Conclusions: PVAC is a multiple neoantigen/CT antigens nanovaccine that personalizes tumor specific antigens and the individual patient’s capacity to respond. Addition of PVAC may prolong progression-free survival (PFS) after the standard of care chemotherapy. Clinical trial information: ChiCTR1800017319 .

MHC genotype, immune repertoire, and tumor immunity all influence spontaneous cancer development and metastasis in spontaneous breast cancer models

Abstract 20 to 30% of breast cancers overexpress ERRB2, encoding the human epidermal growth factor-2 receptor (HER2). Overexpression of HER2 is associated with poorer prognosis, particularly in metastatic disease. Although HER2 therapeutics exists many patients eventually develop uncontrolled tumor growth. The BALB/c-neuT mouse has been a popular model for investigating HER2-positive breast cancer. We have found that immune responsiveness and MHC genotype are important factors in spontaneous tumor development and tumor rejection in the neuT model. To assess the influence of immune response potential on tumor biology we introduced the skg ZAP-70 mutation or the H-2b MHC haplotype into the neuT model. Spontaneous tumors appeared with decreased frequency and metastasis or increased frequency and metastasis, respectively, in comparison to the BALB/c model. H-2b tumors were readily transplantable into the breast fat pads of syngeneic BALB.B-neuT hosts which developed systemic immune abnormalities very similar to those observed in BALB/c - neuT or BALB/c WT mice bearing neuT tumors. However, BALB.B WT hosts initially accepted the grafts, but subsequently rejected them after they were established. Adoptive transfer of splenocytes from BALB.B WT mice which had rejected tumor conferred resistance to the tumor grafts, as well as to spontaneous tumors developing in BALB.B neuT littermates. The strong H-2b-mediated antitumor response in WT mice indicates efficient antigen presentation, and presumably leads to strong tolerance in neuT+ animals. The importance of an intact T cell signaling and MHC genotype indicate a critical role for T cell-mediated immunity and tolerance in the biology of the spontaneously developing tumor and metastasis.

Altering the dendritic cell signature in the lung: a new adjuvant to immune checkpoint inhibitor therapies?

Abstract Lung cancer is the leading cause of cancer-related death. While the recent introduction of immune checkpoint immunotherapies significantly improves patient outcome, many do not respond to this treatment. Dendritic cells (DCs) activate CD8+ T cells to promote the anticancer immune response. Also, in mice, pulmonary CD103+ DC1s specialize in tumour antigen presentation. However, cancer induces an immunosuppressive microenvironment that alters immune function to promote tumor development. Yet, the impact of lung tumor development on DCs remains misunderstood. To study the impact of lung tumour development on the lung dendritic cell signature, Lewis lung carcinoma (LLC) and B16F10 cells (melanoma lung metastasis) were injected intravenously, and lung DC populations analysed by flow cytometry. We observed that in cancer, the proportions of CD103+ DC1 are largely reduced, while an uncharacterized lung CD103+CD11b+ DC population is induced. The latest express surface markers and transcription factors associated with the DC2 population and high levels of PD-L1 and PD-L2 regulatory molecules. This is of crucial importance to immune checkpoint inhibitor therapies, as they rely on the efficient presentation of tumour antigen by DCs to induce T cell responses. In order to promote the anti-tumor capacity of the DC signature, CD103+ DC1s were injected in combination with an immune checkpoint inhibitor (anti-PD-1) in the B16F10 model of resistance to anti-PD1 therapy. The co-injection led to improved sensitivity to immunotherapy. Thus, promoting the replenishment of an anticancer DC environment could be an interesting therapeutic avenue to increase the efficiency of existing immune checkpoint inhibitor therapies.

Vaccine efficacy against primary and metastatic cancer with in vitro-generated CD103+ conventional dendritic cells

Abstract Type 1 conventional dendritic cells (cDC1s) possess efficient antigen presentation and cross-presentation activity, yet the efficacy of immunotherapy utilizingthis population is understudied. We used in vitro-generated CD103+cDC1s in vaccination strategies to test their ability to control melanoma and osteosarcoma tumors. In vitro-generated CD103+cDC1s produced cDC1-associated factors such as IL-12p70 and CXCL10, and demonstrated antigen cross-presentation activity upon stimulation with the Toll-like receptor 3 (TLR3) agonist polyinosinic:polycytidylic acid (poly I:C). In vitro-generated CD103+cDC1s also migrated to tumor-draining lymph nodes (TdLNs) following poly I:C treatment and intratumoral (i.t.) delivery. Vaccination with poly I:C-activated and tumor antigen-loaded CD103+cDC1s enhanced tumor infiltration of tumor antigen-specific and IFN-g+CD8+ T cells, and suppressed melanoma and osteosarcoma growth. CD103+cDC1s showed superior anti-tumor efficacy compared to vaccination with monocyte-derived DCs (MoDCs), and led to complete regression of 100% of osteosarcoma tumors in combination with CTLA-4 antibody-mediated checkpoint blockade. In addition, CD103+cDC1s effectively protected mice from pulmonary melanoma and osteosarcoma metastases. Our data indicate an in vitro-generated CD103+cDC1 vaccine elicits systemic and long-lasting tumor-specific T cell-mediated cytotoxicity, which restrains primary and metastatic tumor growth. The CD103+cDC1 vaccine was superior to MoDCs and enhanced response to immune checkpoint blockade. These results indicate the potential for new immunotherapies based on use of cDC1s alone or in combination with checkpoint blockade.

Induction of CML-specific immune response through cross-presentation triggered by CTP-mediated BCR-ABL-derived peptides.

Although targeted therapy using tyrosine kinase inhibitors (TKIs) has made remarkable progress in treating chronic myeloid leukemia (CML), this disease remains largely incurable, warranting further investigation of new therapeutic strategies. BCR-ABL is a highly specific tumor antigen in CML and provides an attractive opportunity for vaccination therapy. Exogenous antigens must be presented on MHC class I molecules-via a process termed cross-presentation-to activate specific cytotoxic T lymphocyte response. The relative efficiency of cross-presentation is determined in part by the ability of dendritic cells (DCs) to internalize and present antigens. Here, we present a novel tool that uses cytoplasmic transduction peptide (CTP) to facilitate the internalization of antigens by DCs in an endocytosis-independent manner, which greatly enhances the efficiency of antigen presentation, thereby inducing stronger cytotoxic activity to ensure the elimination of CML cells. The data suggest that CTP-fused CML-specific peptides can be applied in vaccination therapies for CML patients.

Vaccine efficacy against primary and metastatic cancer with in vitro-generated CD103+ conventional dendritic cells

BackgroundType 1 conventional dendritic cells (cDC1s) possess efficient antigen presentation and cross-presentation activity, as well as potent T cell priming ability. Tissue-resident cDC1s (CD103+ cDC1s in mice, CD141+ cDC1s in...

Salmonella enterica serovar Enteritidis ghosts displaying a surface FliC adjuvant elicit a robust immune response and effective protection against virulent challenge

Salmonella Enteritidis (SE) is one of the most common culprits of foodborne disease in humans due to its horizontal transmission from infected animals to humans. The development of a safe vaccine against Salmonella would be important for both farm animals and humans concerning disease containment. The SE ghosts carrying FliC were genetically constructed using a special ghost plasmid pJHL184 that co-expressed FliC and the phage lysis gene E. These SE ghosts were characterized by ghost generation efficacy by increasing the culture temperature to “42 °C” in the absence of L-arabinose. This temperature change led to an ghost generation with almost complete lysis of the SE host strain in 48 hs. The expression of FliC was confirmed by Western blot analysis. Also, indirect ELISA was used to prove FliC specific antibody generation in immunized mice. The parenteral adjuvant effect of the FliC antigen was demonstrated by immunizing mice with pJHL184::flC, pJHL184 alone, or PBS alone. The mice were intramuscularly immunized at six weeks of age (n = 8) and boosted after three weeks of primary inoculation. A total of 32 mice were equally divided into four groups. Each group was treated with pJHL-ghosts alone, ghost surface displaying FliC adjuvant, and compared to the PBS and naïve control groups. The immunized mice demonstrated greater IgG and IgA antibody responses than did the PBS control group. Furthermore, the addition of the ghosts to the FliC led to a significant increase in both the humoral and cell-mediated immune responses compared to those in the ghost alone group. Besides, the in vitro antigen uptake and presentation studies revealed efficient antigen presentation on the mouse macrophage cell surfaces. This finding further corroborated the potential efficacy of immune stimulation by SE ghosts. After the virulent challenge, we observed a significant reduction in the bacterial load in the spleen and liver tissues in SE ghosts surface, displaying FliC adjuvant. Our results demonstrate a safe and effective strategy to prevent salmonellosis. They also suggest that the surface expression of flagellin (FliC) significantly enhances antigen-specific humoral and cell-mediated immune responses. This FliC expression can also enhance the protective efficacy of the bacterial ghosts-based vaccine against virulent challenge.

Cholesterol-modified DP7 enhances the effect of individualized cancer immunotherapy based on neoantigens

Personalized cancer vaccines based on neoantigens have become an important research direction in cancer immunotherapy. However, their therapeutic effects are limited by the efficiency of antigen uptake and presentation by antigen presenting cells. Here, the low-toxicity cholesterol-modified antimicrobial peptide (AMP) DP7 (DP7-C), which has dual functions as a carrier and an immune adjuvant, improved the dendritic cell (DC)-based vaccine efficacy. As a delivery carrier, DP7-C can efficiently delivery various antigen peptides into 75–95% of DCs via caveolin- and clathrin-dependent pathways. As an immune adjuvant, DP7-C can induce DC maturation and proinflammatory cytokine release via the TLR2-MyD88-NF-κB pathway and effectively increase antigen presentation efficiency. In addition, DP7-C enhanced the efficacy of DC-based individualized cancer immunotherapy and achieved excellent antitumor effects on mouse tumor models using the OVA antigen peptides and LL2-neoantigens. Excitingly, after DP7-C stimulation, the antigen uptake efficiency of monocytes-derived DCs (MoDCs) in patients with advanced lung cancer increased from 14-40% to 88–98%, the presentation efficiency increased from approximately 15% to approximately 65%, and the proportion of mature MoDCs increased from approximately 20% to approximately 60%. These findings suggest that our approach may be a potentially alternative strategy to produce cancer vaccines designed for individual patients.

Nanoparticles and Vaccine Development.

In spite of the progress of conventional vaccines, improvements are required due to concerns about the low immunogenicity of the toxicity, instability, and the need for multiple administrations of the vaccines. To overcome the mentioned problems, nanotechnology has recently been incorporated into vaccine development. Nanotechnology increasingly plays an important role in vaccine development nanocarrier-based delivery systems that offer an opportunity to increase the cellular and humoral immune responses. The use of nanoparticles in vaccine formulations allows not only enhanced immunogenicity and stability of antigen, but also targeted delivery and slow release. Over the past decade, nanoscale size materials such as virus-like particles, liposomes, ISCOMs, polymeric, inorganic nanoparticles and emulsions have gained attention as potential delivery vehicles for vaccine antigens, which can both stabilize vaccine antigens and act as adjuvants. This advantage is attributable to the nanoscale particle size, which facilitates uptake by Antigen- Presenting Cells (APCs), then leading to efficient antigen recognition and presentation. Modifying the surfaces of nanoparticles with different targeting moieties permits the delivery of antigens to specific receptors on the cell surface, thereby stimulating selective and specific immune responses. This review provides an overview of recent advances in nanovaccinology.

Enhanced translation expands the endo-lysosome size and promotes antigen presentation during phagocyte activation.

The mechanisms that govern organelle adaptation and remodelling remain poorly defined. The endo-lysosomal system degrades cargo from various routes, including endocytosis, phagocytosis, and autophagy. For phagocytes, endosomes and lysosomes (endo-lysosomes) are kingpin organelles because they are essential to kill pathogens and process and present antigens. During phagocyte activation, endo-lysosomes undergo a morphological transformation, going from a collection of dozens of globular structures to a tubular network in a process that requires the phosphatidylinositol-3-kinase-AKT-mechanistic target of rapamycin (mTOR) signalling pathway. Here, we show that the endo-lysosomal system undergoes an expansion in volume and holding capacity during phagocyte activation within 2 h of lipopolysaccharides (LPS) stimulation. Endo-lysosomal expansion was paralleled by an increase in lysosomal protein levels, but this was unexpectedly largely independent of the transcription factor EB (TFEB) and transcription factor E3 (TFE3), which are known to scale up lysosome biogenesis. Instead, we demonstrate a hitherto unappreciated mechanism of acute organelle expansion via mTOR Complex 1 (mTORC1)-dependent increase in translation, which appears to be mediated by both S6Ks and 4E-BPs. Moreover, we show that stimulation of RAW 264.7 macrophage cell line with LPS alters translation of a subset but not all of mRNAs encoding endo-lysosomal proteins, thereby suggesting that endo-lysosome expansion is accompanied by functional remodelling. Importantly, mTORC1-dependent increase in translation activity was necessary for efficient and rapid antigen presentation by dendritic cells. Collectively, we identified a previously unknown and functionally relevant mechanism for endo-lysosome expansion that relies on mTORC1-dependent translation to stimulate endo-lysosome biogenesis in response to an infection signal.

Multiantigenic Nanovaccines: Multiantigenic Nanoformulations Activate Anticancer Immunity Depending on Size (Adv. Funct. Mater. 49/2019)

In article number 1903391, Jianxun Ding and co-workers develop three multiantigenic nanovaccines of different sizes for cancer immunotherapy, which are composed of various imiquimod-loaded poly(lactic-co-glycolic acid) nanoparticles and a cancer cell membrane coating. The smallest nanovaccine shows rapid migration to the draining lymph nodes, achieves efficient antigen presentation to T lymphocytes, and induces antitumor immunity.

Antigen presentation and tumor immunogenicity in cancer immunotherapy response prediction.

Immunotherapy, represented by immune checkpoint inhibitors (ICI), is transforming the treatment of cancer. However, only a small percentage of patients show response to ICI, and there is an unmet need for biomarkers that will identify patients who are more likely to respond to immunotherapy. The fundamental basis for ICI response is the immunogenicity of a tumor, which is primarily determined by tumor antigenicity and antigen presentation efficiency. Here, we propose a method to measure tumor immunogenicity score (TIGS), which combines tumor mutational burden (TMB) and an expression signature of the antigen processing and presenting machinery (APM). In both correlation with pan-cancer ICI objective response rates (ORR) and ICI clinical response prediction for individual patients, TIGS consistently showed improved performance compared to TMB and other known prediction biomarkers for ICI response. This study suggests that TIGS is an effective tumor-inherent biomarker for ICI-response prediction.

Intratumoral immunoglobulin isotypes predict survival in lung adenocarcinoma subtypes

BackgroundThe role of tumor-infiltrating B-cells (TIBs) and intratumorally-produced antibodies in cancer-immunity interactions essentially remains terra incognita. In particular, it remains unexplored how driver mutations could be associated with distinct TIBs signatures and their role in tumor microenvironment.MethodsHere we analyzed associations of immunoglobulin isotypes and clonality with survival in TCGA RNA-Seq data for lung adenocarcinoma (LUAD), stratifying patients into 12 driver mutation and phenotypic tumor subgroups.ResultsWe revealed several unexpected associations between TIBs behavior and prognosis. Abundance and high proportion of IgG1 isotype, and low proportion of IgA among all intratumorally produced immunoglobulins were specifically associated with improved overall survival for KRASmut but not KRASwt LUAD, revealing the first link between a driver mutation and B-cell response. We found specific IgG1 signature associated with long survival, which suggests that particular specificities of IgG1+ TIBs could be beneficial in KRASmut LUAD. In contrast to our previous observations for melanoma, highly clonal IgG1 production by plasma cells had no meaningful effect on prognosis, suggesting that IgG1+ TIBs may exert a beneficial effect in KRASmut cases in an alternative way, such as efficient presentation of cognate antigens or direct B cell attack on tumor cells. Notably, a high proportion of the IgG1 isotype is positively correlated with the non-silent mutation burden both in the general LUAD cohort and in most patient subgroups, supporting a role for IgG1+ TIBs in antigen presentation. Complementing the recent finding that the presence of stromal IgG4-producing cells is associated with a favorable prognosis for patients with stage I squamous cell carcinoma, we show that the abundance of IgG4-producing TIBs likewise has a strong positive effect on overall survival in STK11mut and proximal proliferative subgroups of LUAD patients. We hypothesize that the positive role of IgG4 antibodies in some of the lung cancer subtypes could be associated with reported inability of IgG4 isotype to form immune complexes, thus preventing immunosuppression via activation of the myeloid-derived suppressor cell (MDSC) phenotype.ConclusionsWe discover prominent and distinct associations between TIBs antibody isotypes and survival in lung adenocarcinoma carrying specific driver mutations. These findings indicate that particular types of tumor-immunity relations could be beneficial in particular driver mutation context, which should be taken into account in developing strategies of cancer immunotherapy and combination therapies. Specificity of protective B cell populations in specific cancer subgroups could become a clue to efficient targeted immunotherapies for appropriate cohorts of patients.