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Clinical Cancer Research : An Official... May 2024Combination of chemotherapy with programmed cell death 1 (PD-1) blockade is a front-line treatment for lung cancer. However, it remains unknown whether and how...
PURPOSE
Combination of chemotherapy with programmed cell death 1 (PD-1) blockade is a front-line treatment for lung cancer. However, it remains unknown whether and how chemotherapy affects the response of exhausted CD8 T cells to PD-1 blockade.
EXPERIMENTAL DESIGN
We used the well-established mouse model of T-cell exhaustion with chronic lymphocytic choriomeningitis virus (LCMV) infection to assess the effect of chemotherapy (cisplatin+pemetrexed) on T-cell response to PD-1 blockade, in the absence of the impact of chemotherapy on antigen release and presentation observed in tumor models.
RESULTS
When concomitantly administered with PD-1 blockade, chemotherapy affected the differentiation path of LCMV-specific CD8 T cells from stem-like to transitory effector cells, thereby reducing their expansion and production of IFNγ. After combination treatment, these restrained effector responses resulted in impaired viral control, compared with PD-1 blockade alone. The sequential combination strategy, where PD-1 blockade followed chemotherapy, proved to be superior to the concomitant combination, preserving the proliferative response of exhausted CD8 T cells to PD-1 blockade. Our findings suggest that the stem-like CD8 T cells themselves are relatively unaffected by chemotherapy partly because they are quiescent and maintained by slow self-renewal at the steady state. However, upon the proliferative burst mediated by PD-1 blockade, the accelerated differentiation and self-renewal of stem-like cells may be curbed by concomitant chemotherapy, ultimately resulting in impaired overall CD8 T-cell effector functions.
CONCLUSIONS
In a translational context, we provide a proof-of-concept to consider optimizing the timing of chemo-immunotherapy strategies for improved CD8 T-cell functions. See related commentary by Vignali and Luke, p. 1705.
Topics: Animals; CD8-Positive T-Lymphocytes; Mice; Programmed Cell Death 1 Receptor; Immune Checkpoint Inhibitors; Lymphocytic choriomeningitis virus; Disease Models, Animal; Cisplatin; Lymphocytic Choriomeningitis; Humans; Antineoplastic Combined Chemotherapy Protocols; Mice, Inbred C57BL; Lung Neoplasms
PubMed: 37992307
DOI: 10.1158/1078-0432.CCR-23-1316 -
Journal For Immunotherapy of Cancer Apr 2024Lymphocytic choriomeningitis virus (LCMV) belongs to the Arenavirus family known for inducing strong cytotoxic T-cell responses in both mice and humans. LCMV has been...
BACKGROUND
Lymphocytic choriomeningitis virus (LCMV) belongs to the Arenavirus family known for inducing strong cytotoxic T-cell responses in both mice and humans. LCMV has been engineered for the development of cancer immunotherapies, currently undergoing evaluation in phase I/II clinical trials. Initial findings have demonstrated safety and an exceptional ability to activate and expand tumor-specific T lymphocytes. Combination strategies to maximize the antitumor effectiveness of LCMV-based immunotherapies are being explored.
METHODS
We assessed the antitumor therapeutic effects of intratumoral administration of polyinosinic:polycytidylic acid (poly(I:C)) and systemic vaccination using an LCMV-vector expressing non-oncogenic versions of the E6 and E7 antigens of human papillomavirus 16 (artLCMV-E7E6) in a bilateral model engrafting TC-1/A9 cells. This cell line, derived from the parental TC-1, exhibits low MHC class I expression and is highly immune-resistant. The mechanisms underlying the combination's efficacy were investigated through bulk RNA-seq, flow cytometry analyses of the tumor microenvironment, selective depletions using antibodies and clodronate liposomes, Batf3 deficient mice, and in vivo bioluminescence experiments. Finally, we assessed the antitumor effectiveness of the combination of artLCMV-E7E6 with BO-112, a GMP-grade poly(I:C) formulated in polyethyleneimine, currently under evaluation in clinical trials.
RESULTS
Intratumoral injection of poly(I:C) enhanced the antitumor efficacy of artLCMV-E7E6 in both injected and non-injected tumor lesions. The combined treatment resulted in a significant delay in tumor growth and often complete eradication of several tumor lesions, leading to significantly improved survival compared with monotherapies. While intratumoral administration of poly(I:C) did not impact LCMV vector biodistribution or transgene expression, it significantly modified leucocyte infiltrates within the tumor microenvironment and amplified systemic efficacy through proinflammatory cytokines/chemokines such as CCL3, CCL5, CXCL10, TNF, IFNα, and IL12p70. Upregulation of MHC on tumor cells and a reconfiguration of the gene expression programs related to tumor vasculature, leucocyte migration, and the activation profile of tumor-infiltrating CD8 T lymphocytes were observed. Indeed, the antitumor effect relied on the functions of CD8 T lymphocytes and macrophages. The synergistic efficacy of the combination was further confirmed when BO-112 was included.
CONCLUSION
Intratumoral injection of poly(I:C) sensitizes MHC tumors to the antitumor effects of artLCMV-E7E6, resulting in a potent therapeutic synergy.
Topics: Animals; Humans; Mice; Lymphocytic choriomeningitis virus; Injections, Intralesional; Tissue Distribution; Neoplasms; Immunotherapy; Adjuvants, Immunologic; Tumor Microenvironment; Poly I-C
PubMed: 38631714
DOI: 10.1136/jitc-2023-008287 -
Viruses Feb 2024Lassa virus (LASV) is a zoonotic pathogen endemic throughout western Africa and is responsible for a human disease known as Lassa fever (LF). Historically, LASV has been... (Review)
Review
Lassa virus (LASV) is a zoonotic pathogen endemic throughout western Africa and is responsible for a human disease known as Lassa fever (LF). Historically, LASV has been emphasized as one of the greatest public health threats in West Africa, with up to 300,000 cases and 5000 associated deaths per year. This, and the fact that the disease has been reported in travelers, has driven a rapid production of various vaccine candidates. Several of these vaccines are currently in clinical development, despite limitations in understanding the immune response to infection. Alarmingly, the host immune response has been implicated in the induction of sensorineural hearing loss in LF survivors, legitimately raising safety questions about any future vaccines as well as efficacy in preventing potential hearing loss. The objective of this article is to revisit the importance and prevalence of LF in West Africa, with focus on Nigeria, and discuss current therapeutic approaches and ongoing vaccine development. In addition, we aim to emphasize the need for more scientific studies relating to LF-associated hearing loss, and to promote critical discussion about potential risks and benefits of vaccinating the population in endemic regions of West Africa.
Topics: Humans; Lassa Fever; Lassa virus; Africa, Western; Hearing Loss, Sensorineural; Viral Vaccines; Disease Management
PubMed: 38400041
DOI: 10.3390/v16020266 -
Frontiers in Immunology 2024The host immune response determines the differential outcome of acute or chronic viral infections. The comprehensive comparison of lymphoid tissue immune cells at the...
INTRODUCTION
The host immune response determines the differential outcome of acute or chronic viral infections. The comprehensive comparison of lymphoid tissue immune cells at the single-cell level between acute and chronic viral infections is largely insufficient.
METHODS
To explore the landscape of immune responses to acute and chronic viral infections, single-cell RNA sequencing(scRNA-seq), scTCR-seq and scBCR-seq were utilized to evaluate the longitudinal dynamics and heterogeneity of lymph node CD45 immune cells in mouse models of acute (LCMV Armstrong) and chronic (LCMV clone 13) viral infections.
RESULTS
In contrast with acute viral infection, chronic viral infection distinctly induced more robust NK cells and plasma cells at the early stage (Day 4 post-infection) and acute stage (Day 8 post-infection), respectively. Moreover, chronic viral infection exerted decreased but aberrantly activated plasmacytoid dendritic cells (pDCs) at the acute phase. Simultaneously, there were significantly increased IgA plasma cells (MALT B cells) but differential usage of B-cell receptors in chronic infection. In terms of T-cell responses, Gzma-high effector-like CD8 T cells were significantly induced at the early stage in chronic infection, which showed temporally reversed gene expression throughout viral infection and the differential usage of the most dominant TCR clonotype. Chronic infection also induced more robust CD4 T cell responses, including follicular helper T cells (Tfh) and regulatory T cells (Treg). In addition, chronic infection compromised the TCR diversity in both CD8 and CD4 T cells.
DISCUSSION
In conclusion, gene expression and TCR/BCR immune repertoire profiling at the single-cell level in this study provide new insights into the dynamic and differential immune responses to acute and chronic viral infections.
Topics: Mice; Animals; CD8-Positive T-Lymphocytes; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Persistent Infection; Receptors, Antigen, T-Cell; Lymph Nodes; Sequence Analysis, RNA
PubMed: 38352870
DOI: 10.3389/fimmu.2024.1341985 -
Proceedings of the National Academy of... Aug 2023There are no approved treatments for Lassa fever (LF), which is responsible for thousands of deaths each year in West Africa. A major challenge in developing effective...
There are no approved treatments for Lassa fever (LF), which is responsible for thousands of deaths each year in West Africa. A major challenge in developing effective medical countermeasures against LF is the high diversity of circulating Lassa virus (LASV) strains with four recognized lineages and four proposed lineages. The recent resurgence of LASV in Nigeria caused by genetically distinct strains underscores this concern. Two LASV lineages (II and III) are dominant in Nigeria. Here, we show that combinations of two or three pan-lineage neutralizing human monoclonal antibodies (8.9F, 12.1F, 37.D) known as Arevirumab-2 or Arevirumab-3 can protect up to 100% of cynomolgus macaques against challenge with both lineage II and III LASV isolates when treatment is initiated at advanced stages of disease on day 8 after LASV exposure. This work demonstrates that it may be possible to develop postexposure interventions that can broadly protect against most strains of LASV.
Topics: Animals; Humans; Lassa virus; Lassa Fever; Africa, Western; Antibodies, Monoclonal; Antibodies, Neutralizing; Macaca fascicularis
PubMed: 37590417
DOI: 10.1073/pnas.2304876120 -
Proceedings of the National Academy of... Jul 2023The increasing use of nuclear energy sources inevitably raises the risk of accidental or deliberate radiation exposure and associated immune dysfunction. However, the...
The increasing use of nuclear energy sources inevitably raises the risk of accidental or deliberate radiation exposure and associated immune dysfunction. However, the extent to which radiation exposure impacts memory CD8 T cells, potent mediators of immunity to recurring intracellular infections and malignancies, remains understudied. Using P14 CD8 T cell chimeric mice (P14 chimeras) with an lymphocytic choriomeningitis virus (LCMV) infection model, we observed that sublethal (5Gy) whole-body irradiation (WBI) induced a rapid decline in the number of naive (T) and P14 circulating memory CD8 T cells (T), with the former being more susceptible to radiation-induced numeric loss. While T cell numbers rapidly recovered, as previously described, the number of P14 T cells remained low at least 9 mo after radiation exposure. Additionally, the remaining P14 T in irradiated hosts exhibited an inefficient transition to a central memory (CD62L) phenotype compared to nonirradiated P14 chimeras. WBI also resulted in long-lasting T cell intrinsic deficits in memory CD8 T cells, including diminished cytokine and chemokine production along with impaired secondary expansion upon cognate Ag reencounter. Irradiated P14 chimeras displayed significantly higher bacterial burden after challenge with expressing the LCMV GP epitope relative to nonirradiated controls, likely due to radiation-induced numerical and functional impairments. Taken together, our findings suggest that sublethal radiation exposure caused a long-term numerical, impaired differentiation, and functional dysregulation in preexisting T, rendering previously protected hosts susceptible to reinfection.
Topics: Mice; Animals; Whole-Body Irradiation; Neoplasm Recurrence, Local; CD8-Positive T-Lymphocytes; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Immunologic Memory; Mice, Inbred C57BL
PubMed: 37364124
DOI: 10.1073/pnas.2302785120 -
BMC Microbiology Apr 2024Despite repeated spillover transmission and their potential to cause significant morbidity and mortality in human hosts, the New World mammarenaviruses remain largely... (Review)
Review
Despite repeated spillover transmission and their potential to cause significant morbidity and mortality in human hosts, the New World mammarenaviruses remain largely understudied. These viruses are endemic to South America, with animal reservoir hosts covering large geographic areas and whose transmission ecology and spillover potential are driven in part by land use change and agriculture that put humans in regular contact with zoonotic hosts.We compiled published studies about Guanarito virus, Junin virus, Machupo virus, Chapare virus, Sabia virus, and Lymphocytic Choriomeningitis virus to review the state of knowledge about the viral hemorrhagic fevers caused by New World mammarenaviruses. We summarize what is known about rodent reservoirs, the conditions of spillover transmission for each of these pathogens, and the characteristics of human populations at greatest risk for hemorrhagic fever diseases. We also review the implications of repeated outbreaks and biosecurity concerns where these diseases are endemic, and steps that countries can take to strengthen surveillance and increase capacity of local healthcare systems. While there are unique risks posed by each of these six viruses, their ecological and epidemiological similarities suggest common steps to mitigate spillover transmission and better contain future outbreaks.
Topics: Animals; Humans; Arenaviridae; Arenaviruses, New World; South America
PubMed: 38575867
DOI: 10.1186/s12866-024-03257-w -
MBio Jun 2024Lymphocytic choriomeningitis virus (LCMV) is an enveloped and segmented negative-sense RNA virus classified within the family of the order. LCMV is associated with...
Lymphocytic choriomeningitis virus (LCMV) is an enveloped and segmented negative-sense RNA virus classified within the family of the order. LCMV is associated with fatal disease in immunocompromised populations and, as the prototypical arenavirus member, acts as a model for the many highly pathogenic members of the family, such as Junín, Lassa, and Lujo viruses, all of which are associated with devastating hemorrhagic fevers. To enter cells, the LCMV envelope fuses with late endosomal membranes, for which two established requirements are low pH and interaction between the LCMV glycoprotein (GP) spike and secondary receptor CD164. LCMV subsequently uncoats, where the RNA genome-associated nucleoprotein (NP) separates from the Z protein matrix layer, releasing the viral genome into the cytosol. To further examine LCMV endosome escape, we performed an siRNA screen which identified host cell potassium ion (K) channels as important for LCMV infection, with pharmacological inhibition confirming K channel involvement during the LCMV entry phase completely abrogating productive infection. To better understand the K-mediated block in infection, we tracked incoming virions along their entry pathway under physiological conditions, where uncoating was signified by separation of NP and Z proteins. In contrast, K channel blockade prevented uncoating, trapping virions within Rab7 and CD164-positive endosomes, identifying K as a third LCMV entry requirement. K did not increase GP-CD164 binding or alter GP-CD164-dependent fusion. Thus, we propose that K mediates uncoating by modulating NP-Z interactions within the virion interior. These results suggest K channels represent a potential anti-arenaviral target.IMPORTANCEArenaviruses can cause fatal human disease for which approved preventative or therapeutic options are not available. Here, using the prototypical LCMV, we identified K channels as critical for arenavirus infection, playing a vital role during the entry phase of the infection cycle. We showed that blocking K channel function resulted in entrapment of LCMV particles within late endosomal compartments, thus preventing productive replication. Our data suggest K is required for LCMV uncoating and genome release by modulating interactions between the viral nucleoprotein and the matrix protein layer inside the virus particle.
PubMed: 38874413
DOI: 10.1128/mbio.01684-23 -
Viruses Aug 2023The mammarenavirus Junín (JUNV) is the causative agent of Argentine hemorrhagic fever, a severe disease of public health concern. The most abundant viral protein is the...
The mammarenavirus Junín (JUNV) is the causative agent of Argentine hemorrhagic fever, a severe disease of public health concern. The most abundant viral protein is the nucleoprotein (NP), a multifunctional, two-domain protein with the primary role as structural component of the viral nucleocapsids, used as template for viral polymerase RNA synthesis activities. Here, we report that the C-terminal domain (CTD) of the attenuated Candid#1 strain of the JUNV NP can be purified as a stable soluble form with a secondary structure in line with known NP structures from other mammarenaviruses. We show that the JUNV NP CTD interacts with the viral matrix protein Z in vitro, and that the full-length NP and Z interact with each other in cellulo, suggesting that the NP CTD is responsible for this interaction. This domain comprises an arrangement of four acidic residues and a histidine residue conserved in the active site of exoribonucleases belonging to the DEDDh family. We show that the JUNV NP CTD displays metal-ion-dependent nuclease activity against DNA and single- and double-stranded RNA, and that this activity is impaired by the mutation of a catalytic residue within the DEDDh motif. These results further support this activity, not previously observed in the JUNV NP, which could impact the mechanism of the cellular immune response modulation of this important pathogen.
Topics: Junin virus; Nucleoproteins; Arenaviridae; Catalysis; Exoribonucleases
PubMed: 37766225
DOI: 10.3390/v15091818 -
Cell Reports Feb 2024Viral pandemics and epidemics pose a significant global threat. While macaque models of viral disease are routinely used, it remains unclear how conserved antiviral...
Viral pandemics and epidemics pose a significant global threat. While macaque models of viral disease are routinely used, it remains unclear how conserved antiviral responses are between macaques and humans. Therefore, we conducted a cross-species analysis of transcriptomic data from over 6,088 blood samples from macaques and humans infected with one of 31 viruses. Our findings demonstrate that irrespective of primate or viral species, there are conserved antiviral responses that are consistent across infection phase (acute, chronic, or latent) and viral genome type (DNA or RNA viruses). Leveraging longitudinal data from experimental challenges, we identify virus-specific response kinetics such as host responses to Coronaviridae and Orthomyxoviridae infections peaking 1-3 days earlier than responses to Filoviridae and Arenaviridae viral infections. Our results underscore macaque studies as a powerful tool for understanding viral pathogenesis and immune responses that translate to humans, with implications for viral therapeutic development and pandemic preparedness.
Topics: Animals; Humans; Immunoinformatics; Orthomyxoviridae Infections; Filoviridae; Macaca; Antiviral Agents
PubMed: 38294906
DOI: 10.1016/j.celrep.2024.113706