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Journal For Immunotherapy of Cancer May 2024Tumor-infiltrating lymphocytes (TILs) targeting neoantigens can effectively treat a selected set of metastatic solid cancers. However, harnessing TILs for cancer...
BACKGROUND
Tumor-infiltrating lymphocytes (TILs) targeting neoantigens can effectively treat a selected set of metastatic solid cancers. However, harnessing TILs for cancer treatments remains challenging because neoantigen-reactive T cells are often rare and exhausted, and ex vivo expansion can further reduce their frequencies. This complicates the identification of neoantigen-reactive T-cell receptors (TCRs) and the development of TIL products with high reactivity for patient treatment.
METHODS
We tested whether TILs could be in vitro stimulated against neoantigens to achieve selective expansion of neoantigen-reactive TILs. Given their prevalence, mutant p53 or RAS were studied as models of human neoantigens. An in vitro stimulation method, termed "NeoExpand", was developed to provide neoantigen-specific stimulation to TILs. 25 consecutive patient TILs from tumors harboring p53 or RAS mutations were subjected to NeoExpand.
RESULTS
We show that neoantigenic stimulation achieved selective expansion of neoantigen-reactive TILs and broadened the neoantigen-reactive CD4 and CD8 TIL clonal repertoire. This allowed the effective isolation of novel neoantigen-reactive TCRs. Out of the 25 consecutive TIL samples, neoantigenic stimulation enabled the identification of 16 unique reactivities and 42 TCRs, while conventional TIL expansion identified 9 reactivities and 14 TCRs. Single-cell transcriptome analysis revealed that neoantigenic stimulation increased neoantigen-reactive TILs with stem-like memory phenotypes expressing IL-7R, CD62L, and KLF2. Furthermore, neoantigenic stimulation improved the in vivo antitumor efficacy of TILs relative to the conventional OKT3-induced rapid TIL expansion in p53-mutated or KRAS-mutated xenograft mouse models.
CONCLUSIONS
Taken together, neoantigenic stimulation of TILs selectively expands neoantigen-reactive TILs by frequencies and by their clonal repertoire. NeoExpand led to improved phenotypes and functions of neoantigen-reactive TILs. Our data warrant its clinical evaluation.
TRIAL REGISTRATION NUMBER
NCT00068003, NCT01174121, and NCT03412877.
Topics: Humans; Lymphocytes, Tumor-Infiltrating; Antigens, Neoplasm; Receptors, Antigen, T-Cell; Mice; Immunologic Memory; Animals; Female; Phenotype; Neoplasms
PubMed: 38816232
DOI: 10.1136/jitc-2023-008645 -
Arteriosclerosis, Thrombosis, and... May 2024Atherosclerosis is a complex inflammatory disease in which the adaptive immune response plays an important role. While the overall impact of T and B cells in... (Review)
Review
Atherosclerosis is a complex inflammatory disease in which the adaptive immune response plays an important role. While the overall impact of T and B cells in atherosclerosis is relatively well established, we are only beginning to understand how bidirectional T-cell/B-cell interactions can exert prominent atheroprotective and proatherogenic functions. In this review, we will focus on these T-cell/B-cell interactions and how we could use them to therapeutically target the adaptive immune response in atherosclerosis.
PubMed: 38813700
DOI: 10.1161/ATVBAHA.124.319845 -
Central-European Journal of Immunology 2024There is evidence that influenza vaccination may provide additional benefits by inducing training of innate immunity and increasing humoral responses to heterologous...
There is evidence that influenza vaccination may provide additional benefits by inducing training of innate immunity and increasing humoral responses to heterologous challenges. Immunoglobulin A (IgA) antibodies dominate the early phase of the adaptive response to SARS-CoV-2 infection, but whether their production may be associated with previous influenza vaccination has not been a subject of any study. This study compared serum SARS-CoV-2-specific IgA responses, measured with Microblot-Array assay, in individuals who experienced COVID-19 (N = 1318) and differed in the status of the seasonal influenza vaccine, age, sex, and disease severity. Influenza-vaccinated individuals had a higher seroprevalence of IgA antibodies against nucleocapsid (anti-NP; by 10.1%), receptor-binding domain of spike protein (anti-RBD; by 11.8%) and the S2 subunit of spike protein (anti-S2; by 6.8%). Multivariate analysis, including age, sex, and COVID-19 severity, confirmed that receiving the influenza vaccine was associated with higher odds of being seropositive for anti-NP (OR, 95% CI = 1.57, 1.2-2.0), anti-RBD (OR, 95% CI = 1.6, 1.3-2.0), and anti-S2 (OR, 95% CI = 1.9, 1.4-2.7), as well as being seropositive for at least one anti-SARS-CoV-2 IgA antibody (OR, 95% CI = 1.7, 1.3-2.1) and all three of them (OR, 95% CI = 2.6, 1.7-4.0). Age ≥ 50 years was an additional factor predicting better IgA responses. However, the concentration of particular antibodies in seropositive subjects did not differ in relation to the influenza vaccination status. The study evidenced that influenza vaccination was associated with improved serum IgA levels produced in response to SARS-CoV-2 infection. Further studies are necessary to assess whether trained immunity is involved in the observed phenomenon.
PubMed: 38812601
DOI: 10.5114/ceji.2024.135462 -
Frontiers in Immunology 2024Innate immune training is a metabolic, functional, and epigenetic long-term reprogramming of innate cells triggered by different stimuli. This imprinting also reaches...
INTRODUCTION
Innate immune training is a metabolic, functional, and epigenetic long-term reprogramming of innate cells triggered by different stimuli. This imprinting also reaches hematopoietic precursors in the bone marrow to sustain a memory-like phenotype. Dendritic cells (DCs) can exhibit memory-like responses, enhanced upon subsequent exposure to a pathogen; however, whether this imprinting is lineage and stimulus-restricted is still being determined. Nevertheless, the functional consequences of DCs training on the adaptive and protective immune response against non-infectious diseases remain unresolved.
METHODS
We evaluated the effect of the nontoxic cholera B subunit (CTB), LPS and LTA in the induction of trained immunity in murine DCs revealed by TNFa and LDH expression, through confocal microscopy. Additionally, we obtained bone marrow DCs (BMDCs) from mice treated with CTB, LPS, and LTA and evaluated training features in DCs and their antigen-presenting cell capability using multiparametric cytometry. Finally, we design an experimental melanoma mouse model to demonstrate protection induced by CTB-trained DCs in vivo.
RESULTS
CTB-trained DCs exhibit increased expression of TNFa, and metabolic reprogramming indicated by LDH expression. Moreover, CTB training has an imprint on DC precursors, increasing the number and antigen-presenting function in BMDCs. We found that training by CTB stimulates the recruitment of DC precursors and DCs infiltration at the skin and lymph nodes. Interestingly, training-induced by CTB promotes a highly co-stimulatory phenotype in tumor-infiltrating DCs (CD86+) and a heightened functionality of exhausted CD8 T cells (Ki67+, GZMB+), which were associated with a protective response against melanoma challenge in vivo.
CONCLUSION
Our work indicates that CTB can induce innate immune training on DCs, which turns into an efficient adaptive immune response in the melanoma model and might be a potential immunotherapeutic approach for tumor growth control.
Topics: Animals; Dendritic Cells; Mice; CD8-Positive T-Lymphocytes; Cholera Toxin; Melanoma, Experimental; Mice, Inbred C57BL; Immunity, Innate; Female; Immunologic Memory; Trained Immunity
PubMed: 38812523
DOI: 10.3389/fimmu.2024.1362289 -
Frontiers in Immunology 2024Sex-based differences in immune cell composition and function can contribute to distinct adaptive immune responses. Prior work has quantified these differences in...
Sex-based differences in immune cell composition and function can contribute to distinct adaptive immune responses. Prior work has quantified these differences in peripheral blood, but little is known about sex differences within human lymphoid tissues. Here, we characterized the composition and phenotypes of adaptive immune cells from male and female ex vivo tonsils and evaluated their responses to influenza antigens using an immune organoid approach. In a pediatric cohort, female tonsils had more memory B cells compared to male tonsils direct ex vivo and after stimulation with live-attenuated but not inactivated vaccine, produced higher influenza-specific antibody responses. Sex biases were also observed in adult tonsils but were different from those measured in children. Analysis of peripheral blood immune cells from vaccinated adults also showed higher frequencies of tissue homing CD4 T cells in female participants. Together, our data demonstrate that distinct memory B and T cell profiles are present in male vs. female lymphoid tissues and peripheral blood respectively and suggest that these differences may in part explain sex biases in response to vaccines and viruses.
Topics: Humans; Female; Male; Child; Palatine Tonsil; Adult; Influenza Vaccines; Influenza, Human; Sex Characteristics; Child, Preschool; Adolescent; Antibodies, Viral; Memory B Cells; Organ Specificity; Young Adult; Sex Factors; CD4-Positive T-Lymphocytes; B-Lymphocytes; Immunologic Memory
PubMed: 38812520
DOI: 10.3389/fimmu.2024.1373537 -
Frontiers in Immunology 2024Infection with human papillomavirus (HPV) typically leads to cervical cancer, skin related cancers and many other tumors. HPV is mainly responsible for evading immune... (Review)
Review
Infection with human papillomavirus (HPV) typically leads to cervical cancer, skin related cancers and many other tumors. HPV is mainly responsible for evading immune tumor monitoring in HPV related cancers. Toll like receptors (TLRs) are particular pattern recognition molecules. When the body is facing immune danger, it can lead to innate and direct adaptive immunity. TLR plays an important role in initiating antiviral immune responses. HPV can affect the expression level of TLR and interfere with TLR related signaling pathways, resulting in sustained viral infection and even carcinogenesis. This paper introduces the HPV virus and HPV related cancers. We discussed the present comprehension of TLR, its expression and signaling, as well as its role in HPV infection. We also provided a detailed introduction to immunotherapy methods for HPV related diseases based on TLR agonists. This will provide insights into methods that support the therapeutic method of HPV related conditions with TLR agonists.
Topics: Humans; Toll-Like Receptors; Papillomavirus Infections; Papillomaviridae; Signal Transduction; Neoplasms; Animals; Immunotherapy; Female; Uterine Cervical Neoplasms; Host-Pathogen Interactions
PubMed: 38812510
DOI: 10.3389/fimmu.2024.1407649 -
Frontiers in Immunology 2024Porcine epidemic diarrhea virus (PEDV) causes a highly contagious enteric disease with major economic losses to swine production worldwide. Due to the immaturity of the...
Maternal immunization and vitamin A sufficiency impact sow primary adaptive immunity and passive protection to nursing piglets against porcine epidemic diarrhea virus infection.
Porcine epidemic diarrhea virus (PEDV) causes a highly contagious enteric disease with major economic losses to swine production worldwide. Due to the immaturity of the neonatal piglet immune system and given the high virulence of PEDV, improving passive lactogenic immunity is the best approach to protect suckling piglets against the lethal infection. We tested whether oral vitamin A (VA) supplementation and PEDV exposure of gestating and lactating VA-deficient (VAD) sows would enhance their primary immune responses and boost passive lactogenic protection against the PEDV challenge of their piglets. We demonstrated that PEDV inoculation of pregnant VAD sows in the third trimester provided higher levels of lactogenic protection of piglets as demonstrated by >87% survival rates of their litters compared with <10% in mock litters and that VA supplementation to VAD sows further improved the piglets' survival rates to >98%. We observed significantly elevated PEDV IgA and IgG antibody (Ab) titers and Ab-secreting cells (ASCs) in VA-sufficient (VAS)+PEDV and VAD+VA+PEDV sows, with the latter maintaining higher Ab titers in blood prior to parturition and in blood and milk throughout lactation. The litters of VAD+VA+PEDV sows also had the highest serum PEDV-neutralizing Ab titers at piglet post-challenge days (PCD) 0 and 7, coinciding with higher PEDV IgA ASCs and Ab titers in the blood and milk of their sows, suggesting an immunomodulatory role of VA in sows. Thus, sows that delivered sufficient lactogenic immunity to their piglets provided the highest passive protection against the PEDV challenge. Maternal immunization during pregnancy (± VA) and VA sufficiency enhanced the sow primary immune responses, expression of gut-mammary gland trafficking molecules, and passive protection of their offspring. Our findings are relevant to understanding the role of VA in the Ab responses to oral attenuated vaccines that are critical for successful maternal vaccination programs against enteric infections in infants and young animals.
Topics: Animals; Porcine epidemic diarrhea virus; Female; Swine; Pregnancy; Vitamin A; Coronavirus Infections; Antibodies, Viral; Swine Diseases; Immunity, Maternally-Acquired; Adaptive Immunity; Animals, Newborn; Lactation; Dietary Supplements; Vitamin A Deficiency; Immunization
PubMed: 38812505
DOI: 10.3389/fimmu.2024.1397118 -
Frontiers in Immunology 2024Current SARS-CoV-2 strains continue to mutate and attempt to evade the antibody response elicited by previous exposures and vaccinations. In September of 2022, the first...
INTRODUCTION
Current SARS-CoV-2 strains continue to mutate and attempt to evade the antibody response elicited by previous exposures and vaccinations. In September of 2022, the first updated SARS-CoV-2 vaccines, designed to create immune responses specific for the variants circulating in 2022, were approved. These new vaccines, known commonly as the bivalent boost(er), include mRNA that encodes both the original Wuhan-Hu-1 spike protein as well as the spike protein specific to the Omicron BA.4 and BA.5 variants.
METHODS
We recruited volunteers from University of Massachusetts student, faculty and staff members to provide samples of blood and saliva at four different time points, including pre-boost and three times post boost and analyzed samples for antibody production as well as neutralization of virus.
RESULTS
Our data provide a comprehensive analysis of the antibody response following a single dose of the bivalent boost over a 6-month period and support previous findings that the response induced after the bivalent boost does not create a strong BA.4/BA.5-specific antibody response.
CONCLUSION
We found no evidence of a specific anti-BA.4/BA.5 response developing over time, including in a sub-population of individuals who become infected after a single dose of the bivalent booster. Additionally, we present data that support the use of saliva samples as a reliable alternative to blood for antibody detection against specific SARS-CoV-2 antigens.
Topics: Humans; SARS-CoV-2; Antibodies, Viral; COVID-19; Saliva; COVID-19 Vaccines; Immunization, Secondary; Spike Glycoprotein, Coronavirus; Male; Female; Adult; Antibodies, Neutralizing; Middle Aged; Antibody Formation; Young Adult
PubMed: 38812500
DOI: 10.3389/fimmu.2024.1401209 -
Signal Transduction and Targeted Therapy May 2024Conventional type 1 dendritic cells (cDC1) are the essential antigen-presenting DC subset in antitumor immunity. Suppressing B-cell lymphoma 9 and B-cell lymphoma 9-like...
Conventional type 1 dendritic cells (cDC1) are the essential antigen-presenting DC subset in antitumor immunity. Suppressing B-cell lymphoma 9 and B-cell lymphoma 9-like (BCL9/BCL9L) inhibits tumor growth and boosts immune responses against cancer. However, whether oncogenic BCL9/BCL9L impairs antigen presentation in tumors is still not completely understood. Here, we show that targeting BCL9/BCL9L enhanced antigen presentation by stimulating cDC1 activation and infiltration into tumor. Pharmacological inhibition of BCL9/BCL9L with a novel inhibitor hsBCL9 or Bcl9/Bcl9l knockout mice markedly delayed tumor growth and promoted antitumor CD8 T cell responses. Mechanistically, targeting BCL9/BCL9L promoted antigen presentation in tumors. This is due to the increase of cDC1 activation and tumor infiltration by the XCL1-XCR1 axis. Importantly, using single-cell transcriptomics analysis, we found that Bcl9/Bcl9l deficient cDC1 were superior to wild-type (WT) cDC1 at activation and antigen presentation via NF-κB/IRF1 signaling. Together, we demonstrate that targeting BCL9/BCL9L plays a crucial role in cDC1-modulated antigen presentation of tumor-derived antigens, as well as CD8 T cell activation and tumor infiltration. Targeting BCL9/BCL9L to regulate cDC1 function and directly orchestrate a positive feedback loop necessary for optimal antitumor immunity could serve as a potential strategy to counter immune suppression and enhance cancer immunotherapy.
Topics: Animals; Mice; Dendritic Cells; Antigen Presentation; Transcription Factors; Mice, Knockout; CD8-Positive T-Lymphocytes; Humans; Neoplasms; Receptors, Chemokine
PubMed: 38811552
DOI: 10.1038/s41392-024-01838-9 -
Signal Transduction and Targeted Therapy May 2024The immunoprotective components control COVID-19 disease severity, as well as long-term adaptive immunity maintenance and subsequent reinfection risk discrepancies...
The immunoprotective components control COVID-19 disease severity, as well as long-term adaptive immunity maintenance and subsequent reinfection risk discrepancies across initial COVID-19 severity, remain unclarified. Here, we longitudinally analyzed SARS-CoV-2-specific immune effectors during the acute infection and convalescent phases of 165 patients with COVID-19 categorized by severity. We found that early and robust SARS-CoV-2-specific CD4 and CD8 T cell responses ameliorate disease progression and shortened hospital stay, while delayed and attenuated virus-specific CD8 T cell responses are prominent severe COVID-19 features. Delayed antiviral antibody generation rather than titer level associates with severe outcomes. Conversely, initial COVID-19 severity imprints the long-term maintenance of SARS-CoV-2-specific adaptive immunity, demonstrating that severe convalescents exhibited more sustained virus-specific antibodies and memory T cell responses compared to mild/moderate counterparts. Moreover, initial COVID-19 severity inversely correlates with SARS-CoV-2 reinfection risk. Overall, our study unravels the complicated interaction between temporal characteristics of virus-specific T cell responses and COVID-19 severity to guide future SARS-CoV-2 wave management.
Topics: Humans; COVID-19; SARS-CoV-2; Male; Female; Reinfection; Middle Aged; CD8-Positive T-Lymphocytes; Adult; Severity of Illness Index; Antibodies, Viral; Memory T Cells; Aged; CD4-Positive T-Lymphocytes; Immunologic Memory
PubMed: 38811527
DOI: 10.1038/s41392-024-01867-4