Development Of Immunological Memory Research Articles

The mitochondrial fission protein DRP1 influences memory CD8+ T cell formation and function.

Pharmacological methods for promoting mitochondrial elongation suggest that effector T cells can be altered to support a memory T cell-like metabolic state. Such mitochondrial elongation approaches may enhance the development of immunological memory. Therefore, we hypothesized that deletion of the mitochondrial fission protein dynamin-related protein 1 (DRP1) would lead to mitochondrial elongation and generate a large memory T cell population, an approach that could be exploited to enhance vaccination protocols. We find that, as expected, while deletion of DRP1 from T cells in dLckCre × Drp1flfl does compromise the magnitude and functionality of primary effector CD8+ T cells, a disproportionately large pool of memory CD8+ T cells does form. In contrast to primary effector CD8+ T cells, DRP1-deficient memory dLckCre × Drp1flfl CD8+ T cells mount a secondary response comparable to control memory T cells with respect to kinetics, magnitude, and effector capabilities. Interestingly, the relative propensity to form memory cells in the absence of DRP1 was associated with neither differentiation toward more memory precursor CD8+ T cells nor decreased cellular death of effector T cells. Instead, the tendency to form memory CD8+ T cells in the absence of DRP1 is associated with decreased T cell receptor expression. Remarkably, in a competitive environment with DRP1-replete CD8+ T cells, the absence of DRP1 from CD8+ T cells compromised the generation of primary, memory, and secondary responses, indicating that approaches targeting DRP1 need to be carefully tailored.

Picking up speed: cell cycle regulation during effector CD8+ T cell differentiation

Clonal expansion and development of immunological memory are two hallmarks of adaptive immune responses. Resolving the intricate pathways that regulate cell cycle activity and lead to the generation of diverse effector and memory T cell subsets is essential for improving our understanding of protective T cell immunity. A deeper knowledge of cell cycle regulation in T cells also has translational implications for adoptive cell therapies and vaccinations against infectious diseases. Here, we summarize recent evidence for an early diversification of effector and memory CD8+ T cell fates and discuss how this process is coupled to discrete changes in division speed. We further review technical advances in lineage tracing and cell cycle analysis and outline how these techniques have shed new light on the population dynamics of CD8+ T cell responses, thereby refining our current understanding of the developmental organization of the memory T cell pool.

Naive phenotype antigen-specific CD4 +T cells persist in the memory repertoire after vaccination

Abstract Immunization leads to activation and differentiation of antigen-specific T cells, resulting in the development of immunological memory. However, how the human immune repertoire changes after vaccination remains incompletely understood. Here, we used the live attenuated yellow fever virus (YFV) vaccine or the SARS-CoV-2 mRNA vaccine as models to track post-vaccine kinetics in healthy donors. We quantified and characterized 36 distinct YFV-specific T cell populations and 25 SARS-CoV-2-specific populations by direct ex vivo peptide-MHC tetramer staining. Unexpectedly, we found naïve-phenotype vaccine-specific T cells reappearing after vaccination. On average, 20% of T cells retained a naive phenotype by CD45RO and CCR7 staining although each population had previously expanded after vaccination. A subset of naïve-like T cells expressed other differentiation markers consistent with T memory stem cells (TSCM), but some naïve-like T cells were negative for all memory markers tested. These naïve-phenotype T cells were able to respond to antigens and showed an increased expression of a recent thymic immigrant marker CD31. In conclusion, our results provided the surprising finding that the post-exposure T cell repertoire contains naïve antigen-specific T cells. We plan to test the possibility that the thymus continues to add new T cells into the adult immune repertoire in future experiments. NIH (R01 AI134879) NIH (R01 AO66358)

Effect of estrogen signaling in CD8 T cell mediated antiviral response

Abstract Estrogen, the major female sex hormone has been linked with immune response disparity between males and females. However, the exact mechanism by which estrogen impacts our ability to fight viral infection and development of immunologic memory remains unknown. CD8 T cells represent the primary protective mechanism against viruses and cancer. Here we aim to understand how CD8 T cell mediated antiviral immune response is regulated by estrogen. Systemic LCMV infection in ovariectomized female mice generated lower virus-specific memory CD8 T cells compared to sham surgery controls. To check if this reduction in memory response is CD8 T cell intrinsic, I generated a transgenic virus-specific estrogen receptor-α deficient CD8 mouse line (ESR1 KO). Using a co-adoptive transfer model, I compared the differentiation of ESR1 KO and control CD8 T cells in both systemic LCMV and local influenza infection. The lack of estrogen signaling resulted in reduced abundance of effector CD8 T cells in the context of both infections. ESR1 KO CD8 T cells also displayed reduced cytotoxic ability. In vitrostudies revealed that the CD8 T cell expansion was primarily impacted by the lack of estrogen signaling, whereas activation and cellular apoptosis remain unchanged. Altogether, this suggests a crucial role of sex steroid estrogen in initial effector CD8 T cell differentiation, that has significant ramification for generation of protective immune responses in pathological or physiological estrogen deficiency. Supported by grants from Searle Scholars Foundation, NIH 2P20GM109035, NIH P20GM121298, NIH T32HL134625, NIH T32GM136566

Features of the development of an adaptive antiviral immune response

Both well-known basic cellular and humoral factors of the adaptive antiviral immune response, which play an important role in the effectiveness of immunological reactions to inhibit viral infections, and new factors with which the efficiency of the functioning of cellular and humoral mechanisms of a specific immune response is associated are considered. This is, first of all, the presence of naive T-lymphocytes in the macroorganism, programmed to recognize a specific viral antigen. In addition, this is facilitated by various receptor specificities of T-lymphocytes, of which there are more than 20 million. The diversity of receptor structures was believed to be associated with the functioning of genes that activate recombinase. The development of antiviral cell-mediated mechanisms depends on interleukins 12, interferon-, and the transcriptional activator T-bet. An imbalance in the ratio of T-helper cell types 1 and 2 can lead to memory cell damage. Th-17 plays a central role in controlling the immune response to viral infection. The balance between activated cytotoxic CD-8+/T-helper cells and T-regulatory lymphocytes determines the risk of immunopathology. An excess of effector cells leads to immune-mediated damage, a lack of chronicity of a viral infection. One of the controlling mechanisms that ensure minimal damage to cells and tissues is the assembly of a cytoplasmic protein complex in antigen-presenting cellsinflammasomes. The intensity of inflammatory processes depends on whether the virus is cytopathic. The effectiveness of the humoral immune response is also attributed to the fact that one plasma cell can secrete more than 2,000 antibody molecules per second. One of the powerful properties of the adaptive antiviral immune response is the development of immunological memory by different types of memory T cells. To date, at least three subpopulations of memory T cells with different activation requirements have been identified. Thus, determining how each of these types of memory T-lymphocytes contributes to the long-term antiviral protection of the macroorganism is an urgent task.

Regulation of effector and memory CD8 + T cell differentiation: a focus on orphan nuclear receptor NR4A family, transcription factor, and metabolism.

CD8 + T cells undergo rapid expansion followed by contraction and the development of memory cells after their receptors are activated. The development of immunological memory following acute infection is a complex phenomenon that involves several molecular, transcriptional, and metabolic mechanisms. As memory cells confer long-term protection and respond to secondary stimulation with strong effector function, understanding the mechanisms that influence their development is of great importance. Orphan nuclear receptors, NR4As, are immediate early genes that function as transcription factors and bind with the NBRE region of chromatin. Interestingly, the NBRE region of activated CD8 + T cells is highly accessible at the same time the expression of NR4As is induced. This suggests a potential role of NR4As in the early events post T cell activation that determines cell fate decisions. In this review, we will discuss the influence of NR4As on the differentiation of CD8 + T cells during the immune response to acute infection and the development of immunological memory. We will also discuss the signals, transcription factors, and metabolic mechanisms that control cell fate decisions. HIGHLIGHTS: Memory CD8 + T cells are an essential subset that mediates long-term protection after pathogen encounters. Some specific environmental cues, transcriptional factors, and metabolic pathways regulate the differentiation of CD8 + T cells and the development of memory cells. Orphan nuclear receptor NR4As are early genes that act as transcription factors and are highly expressed post-T cell receptor activation. NR4As influence the effector function and differentiation of CD8 + T cells and also control the development of immunological memory following acute infection.

Protozoan co-infections and parasite influence on the efficacy of vaccines against bacterial and viral pathogens.

A wide range of protozoan pathogens either transmitted by vectors (Plasmodium, Babesia, Leishmania and Trypanosoma), by contaminated food or water (Entamoeba and Giardia), or by sexual contact (Trichomonas) invade various organs in the body and cause prominent human diseases, such as malaria, babesiosis, leishmaniasis, trypanosomiasis, diarrhea, and trichomoniasis. Humans are frequently exposed to multiple pathogens simultaneously, or sequentially in the high-incidence regions to result in co-infections. Consequently, synergistic or antagonistic pathogenic effects could occur between microbes that also influences overall host responses and severity of diseases. The co-infecting organisms can also follow independent trajectory. In either case, co-infections change host and pathogen metabolic microenvironments, compromise the host immune status, and affect microbial pathogenicity to influence tissue colonization. Immunomodulation by protozoa often adversely affects cellular and humoral immune responses against co-infecting bacterial pathogens and promotes bacterial persistence, and result in more severe disease symptoms. Although co-infections by protozoa and viruses also occur in humans, extensive studies are not yet conducted probably because of limited animal model systems available that can be used for both groups of pathogens. Immunosuppressive effects of protozoan infections can also attenuate vaccines efficacy, weaken immunological memory development, and thus attenuate protection against co-infecting pathogens. Due to increasing occurrence of parasitic infections, roles of acute to chronic protozoan infection on immunological changes need extensive investigations to improve understanding of the mechanistic details of specific immune responses alteration. In fact, this phenomenon should be seriously considered as one cause of breakthrough infections after vaccination against both bacterial and viral pathogens, and for the emergence of drug-resistant bacterial strains. Such studies would facilitate development and implementation of effective vaccination and treatment regimens to prevent or significantly reduce breakthrough infections.

Abstract 4224: BPT-143: a fully synthetic alpha-dead IL-2 with a best-in-class preclinical pharmacodynamic and efficacy profile supporting first-in-human clinical development

Abstract High-dose recombinant IL-2 (aldesleukin) is approved for treatment of advanced melanoma and renal cell carcinoma, however, major limitations restrict its therapeutic use. Wild-type IL-2 acts via binding to the medium-affinity IL-2 receptor βγ (IL2Rβγ) expressed in CD8+ T effector cells and NK cells. At the same time, its efficacy is dampened due to strong activation of regulatory T cells (Treg) expressing the high-affinity IL-2 receptor αβγ (IL2Rαβγ). Furthermore, binding to CD25/IL2Rα on endothelial cells and type 2 innate lymphoid cells is thought to be involved in the induction of severe toxicity including vascular leak syndrome (VLS). In addition, aldesleukin exhibits a very short half-life that, combined with its safety risks, requires a burdensome inpatient treatment schedule. We set out to rationally design a variant of human IL-2 that addresses and overcomes the major limitations of aldesleukin. Using our chemical protein synthesis technology, we introduced select modified amino acids including site-specific chemical conjugation handles to optimize the properties of IL-2 for cancer therapy while maintaining high homology to the wild-type IL-2 sequence. Bright Peak’s enhanced cytokine shows increased binding to CD122/IL2Rβ and does not interact with CD25/IL2Rα to improve safety and prevent the preferential activation of Tregs compared to CD8+ T effector cells. Site-specific conjugation to a 30 kDa PEG for half-life extension resulted in the generation of BPT-143, which is equipotent to aldesleukin in activating CD8+ T cells in vitro. In mice, BPT-143 induces a strong expansion of CD8+ T cells with only transient and minor effects on Tregs in vivo and exhibits improved PK properties allowing for a convenient dosing schedule. In the syngeneic CT26 tumor model, BPT-143 showed strong anti-tumor efficacy as a single agent as well as enhanced efficacy in combination with an anti-PD-1 antibody. BPT-143 induced a 55% complete response rate and, upon tumor re-challenge, all cured animals rejected CT26 tumor cells indicating the development of immunologic memory. In multiple-dose PK/PD studies in non-human primates (NHP), BPT-143 was well tolerated and induced robust and repeated expansion of CD8+ T cells, CD4+ conventional T cells and NK cells while showing only negligible effects on Tregs and eosinophils. Both in vivo efficacy studies in murine tumor models as well as PD effects observed in NHP indicate that BPT-143 has a best-in-class profile among “not-alpha” IL-2 compounds currently in development. IND-enabling studies are ongoing and a first in human trial is planned to start in 2022. Citation Format: Jean-Philippe Carralot, Rubén Alvarez Sanchez, Matilde Arévalo Ruiz, Magali Muller, Vijaya R. Pattabiraman, Bertolt Kreft. BPT-143: a fully synthetic alpha-dead IL-2 with a best-in-class preclinical pharmacodynamic and efficacy profile supporting first-in-human clinical development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4224.

Abstract 4252: PD-L1-targeted ISAC combines myeloid cell activation, immune-checkpoint inhibition and ADCP to improve anti-tumor efficacy over anti-PD-L1 antibodies in preclinical models

Abstract INTRODUCTION: Immune-stimulating antibody conjugates (ISACs) consist of tumor-targeting antibodies conjugated to immune stimulants and are designed to activate the innate and adaptive immune systems against tumor cells following systemic administration. PD-L1 is an immune checkpoint that regulates anti-tumor T cell responses and is expressed on tumor cells as well as tumor-infiltrating immune cells across many tumor types. Here we show that PD-L1-targeted TLR7/8 ISACs elicit robust myeloid cell activation and can act through PD-L1 on either tumor or immune cells to improve anti-tumor responses compared to anti-PD-L1 treatment in preclinical tumor models. METHODS: A panel of proprietary anti-PD-L1 ISACs was evaluated for target-dependent in vitro myeloid cell activation by co-culturing PD-L1 expressing tumor cells with cDC-enriched primary myeloid cells. Anti-tumor efficacy of anti-PD-L1 ISACs was evaluated in vivo in both syngeneic and xenograft tumor models. MB49-PD-L1 KO cells were generated by knocking-out PD-L1 gene using CRISPR/Cas9 system. RESULTS: Anti-PD-L1 antibodies induced robust ADCP by myeloid effector cells and PD-L1/PD-1 blockade in vitro and in vivo. The conjugated PD-L1 ISACs induced robust, target-dependent activation of myeloid cells when co-cultured with tumor cells expressing PD-L1 at physiological levels, as measured by increased secretion of such cytokines as IL-12p70, TNFα, and IFNγ. Systemically administered surrogate PD-L1 ISACs were well tolerated in mice and showed improved anti-tumor efficacy over anti-PD-L1 antibodies, with significant tumor growth delay or complete responses frequently observed in syngeneic (e.g., MB49, MC38-hPD-L1) as well as xenograft (e.g., HCC1954-hPD-L1) tumor models. The improved in vivo efficacy of PD-L1 ISACs was sustained even in the absence of PD-L1 expression on tumor cells in syngeneic MB49-PD-L1 KO model suggesting that PD-L1 ISAC can induce its mechanism of action also through PD-L1 on myeloid cells. No tumor growth was observed after rechallenging mice previously cured with PD-L1 ISACs indicating development of immunological memory following the ISAC treatment. CONCLUSIONS: These preclinical data demonstrate the potential of a PD-L1-targeted ISAC as a novel multifunctional therapeutic that may improve efficacy of PD-L1/PD-1 inhibition by combining three mechanisms of action into a single molecule: TLR-mediated myeloid cell activation, T cell activation through immune-checkpoint inhibition as well as ADCP. Citation Format: Justin A. Kenkel, Rishali Gadkari, Po Y. Ho, Lisa K. Blum, Romas Kudirka, Karla A. Henning, William G. Mallet, Jennifer E. Melrose, Ganapathy Sarma, Steven J. Chapin, Matthew Zhou, Suprit Deol, Cindy Kreder, Yuyi Shen, Bruce Hug, Puneet Anand, Arthur Lee, Hai Li, Shelley E. Ackerman, Brian S. Safina, David Dornan, Michael N. Alonso, Marcin Kowanetz. PD-L1-targeted ISAC combines myeloid cell activation, immune-checkpoint inhibition and ADCP to improve anti-tumor efficacy over anti-PD-L1 antibodies in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4252.

Emerging Concepts in Innate Lymphoid Cells, Memory, and Reproduction

Members of the innate immune system, innate lymphoid cells (ILCs), encompass five major populations (Natural Killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer cells) whose functions include defense against pathogens, surveillance of tumorigenesis, and regulation of tissue homeostasis and remodeling. ILCs are present in the uterine environment of humans and mice and are dynamically regulated during the reproductive cycle and pregnancy. These cells have been repurposed to support pregnancy promoting maternal immune tolerance and placental development. To accomplish their tasks, immune cells employ several cellular and molecular mechanisms. They have the capacity to remember a previously encountered antigen and mount a more effective response to succeeding events. Memory responses are not an exclusive feature of the adaptive immune system, but also occur in innate immune cells. Innate immune memory has already been demonstrated in monocytes/macrophages, neutrophils, dendritic cells, and ILCs. A population of decidual NK cells characterized by elevated expression of NKG2C and LILRB1 as well as a distinctive transcriptional and epigenetic profile was found to expand during subsequent pregnancies in humans. These cells secrete high amounts of interferon-γ and vascular endothelial growth factor likely favoring placentation. Similarly, uterine ILC1s in mice upregulate CXCR6 and expand in second pregnancies. These data provide evidence on the development of immunological memory of pregnancy. In this article, the characteristics, functions, and localization of ILCs are reviewed, emphasizing available data on the uterine environment. Following, the concept of innate immune memory and its mechanisms, which include epigenetic changes and metabolic rewiring, are presented. Finally, the emerging role of innate immune memory on reproduction is discussed. Advances in the comprehension of ILC functions and innate immune memory may contribute to uncovering the immunological mechanisms underlying female fertility/infertility, placental development, and distinct outcomes in second pregnancies related to higher birth weight and lower incidence of complications.

Vaccines Against COVID-19: A Review.

As a result of the COVID-19 pandemic, various joint efforts have been made to support the creation of vaccines. Different projects have been under development, of which some are in the clinical evaluation stage and others in are in phase III with positive results. The aim of this paper was to describe the current situation of the development and production of vaccines available to the population to facilitate future research and continue developing and proposing ideas for the benefit of the population. So, we carried out a systematic review using databases such as PubMed, ScienceDirect, SciELO, and MEDLINE, including keywords such as “vaccines,” “COVID-19,” and “SARS-CoV-2”. We reviewed the development and production of the anti-COVID vaccine and its different platforms, the background leading to the massive development of these substances, and the most basic immune aspects for a better understanding of their physiological activity and the immune response in those who receive the vaccine. We also analyzed immunization effects in populations with any medical or physiological conditions (such as immunosuppression, people with comorbidities, and pregnancy), as well as the response to immunization with heterologous vaccines and the hybrid immunity (the combination of natural immunity to SARS-CoV-2 with immunity generated by the vaccine). Likewise, we address the current situation in Mexico and its role in managing the vaccination process against SARS-CoV-2 at the national and international levels. There are still many clinical and molecular aspects to be described, such as the duration of active immunity and the development of immunological memory, to mention some of the most important ones. However, due to the short time since the global vaccination roll-out and that it has been progressive (not counting children and people with medical conditions), it is premature to say whether a second vaccination schedule will be necessary for the near future. Thus, it is essential to continue with health measures.

Review on Immunity to Fungal Infections in Animals

The occurrence of mycosis is relatively uncommon in healthy and immunocompetent hosts. But now a days, the incidence of fungal infections are increasing and there is no effective vaccine for fungal infections in contrast to bacterial and viral diseases. And also, available antifungal drugs are not effective to treat infected animals. Understanding the immunity against fungal infections is of interest which can contribute more for therapeutic and vaccine development. Therefore, this review focuses on the immune components involved in clearing fungal pathogens. Disease outcome is a result of host-pathogen interactions. Immunity is the body’s resistance to infection. Innate and acquired immune systems are involved to eliminate animal fungal infections. Innate immunity is not specific. It is the first line of defense, with genetically encoded receptors that identify greatly conserved pathogen-associated molecular patterns. Physical barriers, phagocytic cells, chemotactic factors and natural killer cells are some of the innate defense mechanisms. Adaptive immunity is specific. Lymphocytes have a unique and specific antigen receptor. It can be a humoral or cellular type of immune system. In adaptive immunity, there is a development of immunological memory in the host after exposure to a pathogen. However, there are no effective vaccines and antifungal drugs. So it causes high morbidity and mortality in animals and fungal pathogens have become a significant clinical challenge, leading to a global threat to controlling fungal infections. Therefore, good management of animals and treating concurrent infections strengthens their immunity. Besides, promoting research into fungal infections to develop new diagnostics, anti-fungal drugs and vaccines are recommended.

Infection with SARS-CoV-2 primes immunological memory in human nasal-associated lymphoid tissue

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has resulted in considerable morbidity and mortality in humans. Little is known regarding the development of immunological memory following SARS-CoV-2 infection or whether immunological memory can provide long-lasting protection against reinfection. Urgent need for vaccines is a considerable issue for all governments worldwide. MethodsA total of 39 patients were recruited in this study. Tonsillar mononuclear cells (MNCs) were co-cultured in RPMI medium and stimulated with the full-length SARS-CoV-2 spike protein in the presence and absence of a CpG-DNA adjuvant. An enzyme-linked immunosorbent assay (ELISA) was utilised to measure the specific antibody response to the spike protein in the cell culture supernatants. ResultsThe SARS-CoV-2 spike protein primed a potent memory B cell-mediated immune response in nasal-associated lymphoid tissue (NALT) from patients previously infected with the virus. Additionally, spike protein combined with the CpG-DNA adjuvant induced a significantly increased level of specific anti-spike protein IgG antibody compared with the spike protein alone (p < 0.0001, n = 24). We also showed a strong positive correlation between the specific anti-spike protein IgG antibody level in a serum samples and that produced by MNCs derived from the same COVID-19-recovered patients following stimulation (r = 0.76, p = 0.0002, n = 24). ConclusionIndividuals with serological evidence of previous SARS-CoV-2 exposure showed a significant anti-spike protein-specific memory humoral immune response to the viral spike protein upon stimulation. Additionally, our results demonstrated the functional response of NALT-derived MNCs to the viral spike protein. CpG-DNA adjuvant combined with spike protein induced significantly stronger humoral immune responses than the spike protein alone. These data indicate that the S protein antigen combined with CpG-DNA adjuvant could be used as a future vaccine candidate.

Abstract 1735: The potent and selective MERTK/AXL inhibitor PF-5807/ARRY-067 activates dendritic cells to cross-prime CD8+ T cells for anti-tumor activity

Abstract The TAM family of receptor tyrosine kinases (MERTK, AXL, and TYRO3) are expressed on DCs and macrophages, and they serve a critical role in efferocytosis, by which apoptotic bodies are cleared by engulfment. Their activation drives phagocytic activity concomitant to promoting an immuno-suppressive, tolerogenic state in DCs and the M2 polarization of macrophages. This dual signaling mechanism allows for the clearance of cells undergoing non-pathologic apoptotic turnover without inappropriately breaking self-tolerance and driving auto-immunity. Unlike most immuno-therapy targets, the KOs of the TAM kinases, PD-1, and CTLA-4 share common auto-immune disease phenotypes such as splenomegaly, immune infiltration of the liver, arthritis, and lupus. Furthermore, viruses have evolved to promote PD-1/CTLA-4 signaling to suppress the anti-viral immune response, and they similarly target the TAM receptors via apoptotic mimicry to reduce the inflammatory response. This confluence of immune phenotypes provided the biological rationale for the discovery of PF-5807/ARRY-067, a potent and selective inhibitor of MERTK/AXL as a DC-activating immuno-oncology therapeutic. Based on the IC50 for inhibition of phospho-MERTK/AXL in cell-based assays, our mouse PK and PK/PD studies determined that 50 mg/kg PF-5807 provided IC90 plasma coverage for 12 hours. This PK profile supported a twice-daily dosing schedule for maintaining continuous suppression of MERTK and AXL, which was used for mechanistic and efficacy studies in mouse models. To investigate DC and T cell responses to PF-5807, mice were adoptively-transferred with OT-I T cells and challenged with ovalbumin immunization; flow cytometry analysis indicated that PF-5807 treatment increased the fraction of activated, Class II MHC-positive DCs, as well as cross-primed IFNγ+ TNFα+ OT-I T cells. Also, we found that cytotoxic T lymphocytes were necessary for tumor control in the E0771 mouse syngeneic tumor model, as depletion of CD8+ T cells abrogated all activity by PF-5807 in inhibiting tumor growth. This anti-tumor activity was further demonstrated in the MC-38 and EMT6 tumor models, where single agent PF-5807 effected 57-88% TGI and a 13-38% cure rate, while combination with PD-1 blockade drove 99-100% TGI and a 75-100% cure rate. Finally, these complete responders rejected tumor re-challenge without further treatment, resulting in extended survival and durable cures that corroborate the development of immunologic memory. Therefore, we find that PF-5807 activates DCs to cross-prime CD8+ T cells, which are necessary for tumor control and are likely responsible for the establishment of tumor-specific memory T cells. PF-5807 is currently in an ongoing Phase I clinical trial in patients with advanced or metastatic solid tumors, with the intent to explore combination with anti-PD-1/anti-PD-L1 antibodies. Citation Format: Jim Wong, Jacqueline Harrison, Karyn Bouhana, Nhan Nguyen, Namir Shaabani, Vincent F. Vartabedian, LouAnn Cable, Robert Rieger, Lisa Pieti Opie, Shelley Allen, Adam Cook, Joshua Dahlke, Ronald Hinklin, David Chantry, Shannon Winski, John Teijaro. The potent and selective MERTK/AXL inhibitor PF-5807/ARRY-067 activates dendritic cells to cross-prime CD8+ T cells for anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1735.

Characterization of the robust humoral immune response to GSK2618960, a humanized anti-IL-7 receptor monoclonal antibody, observed in healthy subjects in a Phase 1 study

Interleukin-7 (IL-7) signaling modulates T cell activity and is implicated in numerous autoimmune diseases. An anti-IL-7 receptor monoclonal antibody (GSK2618960) biotherapeutic was evaluated in healthy subjects for safety, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity in a single-dose escalation phase I study. We found that antibodies against GSK2618960 (i.e., anti-drug antibodies or ADA) developed in 83% and 100% of GSK2618960-treated subjects in the 0.6 and 2.0 mg/kg dose cohorts, respectively. Of the ADA positive subjects, 64% (7 of 11) had detectable neutralizing activity. Further investigation revealed the presence of GSK2618960-specific memory B cells, indicating the development of immunological memory for the ADAs. Ex vivo stimulation of peripheral blood mononuclear cell (PBMC) samples demonstrated a relatively strong CD4+ T cell proliferation response to GSK2618960 as compared to the control anti-RSV antibody (which is known to have only low immunogenic potential), confirming the high immunogenic potential of GSK2618960. Furthermore, GSK2618960 was found to bind in vitro monocyte-derived dendritic cells (DCs). GSK2618960 treatment of PBMCs increased the proportion of DC cells showing an increase in expression of CD83, CD86 and CD209, which indicated enhanced DC differentiation and activation relative to the isotype control anti-β amyloid antibody. Collectively, the evidence supports that the high incidence of observed clinical immunogenicity was likely related to the receptor-mediated activity by GSK2618960.

SRC family kinase (SFK) inhibitor dasatinib improves the antitumor activity of anti-PD-1 in NSCLC models by inhibiting Treg cell conversion and proliferation

IntroductionThe use of immune-checkpoint inhibitors has drastically improved the management of patients with non-small cell lung cancer (NSCLC), but innate and acquired resistances are hurdles needed to be solved. Immunomodulatory...

The Use of Extracellular Membrane Vesicles for Immunization against Francisellosis in Nile Tilapia (Oreochromis niloticus) and Atlantic Cod (Gadus morhua L.).

Francisellosis in fish is caused by the facultative intracellular Gram-negative bacterial pathogens Francisella noatunensis ssp. noatunensis and Francisella orientalis. The disease is affecting both farmed and wild fish worldwide and no commercial vaccines are currently available. In this study, we tested isolated membrane vesicles (MVs) as possible vaccine candidates based on previous trials in zebrafish (Danio rerio) indicating promising vaccine efficacy. Here, the MV vaccine-candidates were tested in their natural hosts, Atlantic cod (Gadus morhua L.) and Nile tilapia (Oreochromis niloticus). Injection of MVs did not display any toxicity or other negative influence on the fish and gene expression analysis indicated an influence on the host immune response. However, unlike in other tested fish species, a protective immunity following vaccine application and immunization period could not be detected in the Atlantic cod or tilapia. Further in vivo studies are required to achieve a better understanding of the development of immunological memory in different fish species.

The new role for an old guy: MYC as an immunoplayer.

As an oncogene, myelocytomatosis oncogene (MYC) is implicated in the concept of "oncogene addiction," where switching off the oncogene leads to the cell cycle arrest and cell differentiation. However, recent data suggest that MYC also controls the establishment of the tumour microenvironment and that "oncogene addiction" actually has a strong immune background. Evaluation of the MYC role in the immunoediting process led to the speculation that cancer just uses and distorts the physiological mechanism by which MYC normally prevents rapidly proliferating cells from the elicitation of an autoimmune response. Concordantly, elevated levels of MYC and induction of immunosuppressive molecules are observed during the processes of growth and development, tissue repair, placenta development, and so forth, implying that MYC may be involved in saving regular physiologically proliferating cells from the immune system attack. Even more, a growing body of evidence suggests MYC involvement in the shaping of the adaptive immune response, immunological memory development, and establishment of immunotolerance. This paper offers an overview of MYC actions in the context of modulation of the immune response in pathological and physiological conditions. The determination of such a new role for a well-known oncogene opens new perspectives in biomedicine, and consequently, in the treatment of various pathological conditions.

A geroscience perspective on immune resilience and infectious diseases: a potential case for metformin.

We are in the midst of the global pandemic. Though acute respiratory coronavirus (SARS-COV2) that leads to COVID-19 infects people of all ages, severe symptoms and mortality occur disproportionately in older adults. Geroscience interventions that target biological aging could decrease risk across multiple age-related diseases and improve outcomes in response to infectious disease. This offers hope for a new host-directed therapeutic approach that could (i) improve outcomes following exposure or shorten treatment regimens; (ii) reduce the chronic pathology associated with the infectious disease and subsequent comorbidity, frailty, and disability; and (iii) promote development of immunological memory that protects against relapse or improves response to vaccination. We review the possibility of this approach by examining available evidence in metformin: a generic drug with a proven safety record that will be used in a large-scale multicenter clinical trial. Though rigorous translational research and clinical trials are needed to test this empirically, metformin may improve host immune defenses and confer protection against long-term health consequences of infectious disease, age-related chronic diseases, and geriatric syndromes.

Synthetic High-density Lipoprotein Nanodiscs for Personalized Immunotherapy Against Gliomas.

Gliomas are brain tumors with dismal prognoses. The standard-of-care treatments for gliomas include surgical resection, radiation, and temozolomide administration; however, they have been ineffective in providing significant increases in median survival. Antigen-specific cancer vaccines and immune checkpoint blockade may provide promising immunotherapeutic approaches for gliomas. We have developed immunotherapy delivery vehicles based on synthetic high-density lipoprotein (sHDL) loaded with CpG, a Toll-like receptor-9 agonist, and tumor-specific neoantigens to target gliomas and elicit immune-mediated tumor regression. We demonstrate that vaccination with neoantigen peptide-sHDL/CpG cocktail in combination with anti-PD-L1 immune checkpoint blocker elicits robust neoantigen-specific T-cell responses against GL261 cells and eliminated established orthotopic GL261 glioma in 33% of mice. Mice remained tumor free upon tumor cell rechallenge in the contralateral hemisphere, indicating the development of immunologic memory. Moreover, in a genetically engineered murine model of orthotopic mutant IDH1 (mIDH1) glioma, sHDL vaccination with mIDH1 neoantigen eliminated glioma in 30% of animals and significantly extended the animal survival, demonstrating the versatility of our approach in multiple glioma models. Overall, our strategy provides a general roadmap for combination immunotherapy against gliomas and other cancer types.