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Cell Mar 2023Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate...
Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate multiple branches of the immune system may eliminate escape variants. Here, we show that melanoma-specific CD4 T cell therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate melanomas containing antigen escape variants. As expected, early on-target recognition of melanoma antigens by tumor-specific CD4 T cells was required. Surprisingly, complete tumor eradication was dependent on neutrophils and partly dependent on inducible nitric oxide synthase. In support of these findings, extensive neutrophil activation was observed in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade. Transcriptomic and flow cytometry analyses revealed a distinct anti-tumorigenic neutrophil subset present in treated mice. Our findings uncover an interplay between T cells mediating the initial anti-tumor immune response and neutrophils mediating the destruction of tumor antigen loss variants.
Topics: Mice; Animals; T-Lymphocytes; Neutrophils; Antigenic Drift and Shift; Immunotherapy; Melanoma; CTLA-4 Antigen
PubMed: 37001503
DOI: 10.1016/j.cell.2023.03.007 -
Nature Reviews. Microbiology Jul 2021Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively... (Review)
Review
Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively neutral, a small proportion will affect functional properties and may alter infectivity, disease severity or interactions with host immunity. The emergence of SARS-CoV-2 in late 2019 was followed by a period of relative evolutionary stasis lasting about 11 months. Since late 2020, however, SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations, in the context of 'variants of concern', that impact virus characteristics, including transmissibility and antigenicity, probably in response to the changing immune profile of the human population. There is emerging evidence of reduced neutralization of some SARS-CoV-2 variants by postvaccination serum; however, a greater understanding of correlates of protection is required to evaluate how this may impact vaccine effectiveness. Nonetheless, manufacturers are preparing platforms for a possible update of vaccine sequences, and it is crucial that surveillance of genetic and antigenic changes in the global virus population is done alongside experiments to elucidate the phenotypic impacts of mutations. In this Review, we summarize the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets.
Topics: Amino Acids; Antigenic Variation; COVID-19; COVID-19 Vaccines; Epitopes; Humans; Immune Evasion; Mutation; Protein Conformation; SARS-CoV-2; Spike Glycoprotein, Coronavirus
PubMed: 34075212
DOI: 10.1038/s41579-021-00573-0 -
Frontiers in Immunology 2020Protective vaccines for hypervariable pathogens are urgently needed. It has been proposed that amputating highly variable epitopes from vaccine antigens would induce the...
Protective vaccines for hypervariable pathogens are urgently needed. It has been proposed that amputating highly variable epitopes from vaccine antigens would induce the production of broadly protective antibodies targeting conserved epitopes. However, so far, these approaches have failed, partially because conserved epitopes are occluded and partially because co-localizing patterns of immunodominance and antigenic variability render variable epitopes the primary target for antibodies in natural infection. In this Perspective, to recast the challenge of vaccine development for hypervariable pathogens, I evaluate convergent mechanisms of adaptive variation, such as intrahost immune-mediated diversification, spatiotemporally defined antigenic space, and infection-enhancing cross-immunoreactivity. The requirements of broadly protective immune responses targeting variable pathogens are formulated in terms of cross-immunoreactivity, stoichiometric thresholds for neutralization, and the elicitation of antibodies targeting physicochemically conserved signatures within sequence variable domains.
Topics: Animals; Antibodies, Neutralizing; Antigenic Variation; Humans; Immunodominant Epitopes; Mutation; Vaccination; Viral Envelope Proteins; Viral Vaccines; Virus Diseases
PubMed: 33013870
DOI: 10.3389/fimmu.2020.02057 -
Nature Medicine Sep 2023B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T...
B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging data report that downregulation of G-protein-coupled receptor family C group 5 member D (GPRC5D) protein often occurs at relapse after anti-GPRC5D CAR T therapy. To examine the tumor-intrinsic factors that promote MM antigen escape, we performed combined bulk and single-cell whole-genome sequencing and copy number variation analysis of 30 patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapy. In two cases, MM relapse post-TCE/CAR T therapy was driven by BCMA-negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss. In another five cases of relapse, newly detected, nontruncating, missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCE therapies, despite detectable surface BCMA protein expression. In the present study, we also report four cases of MM relapse with biallelic mutations of GPRC5D after anti-GPRC5D TCE therapy, including two cases with convergent evolution where multiple subclones lost GPRC5D through somatic events. Immunoselection of BCMA- or GPRC5D-negative or mutant clones is an important tumor-intrinsic driver of relapse post-targeted therapies. Mutational events on BCMA confer distinct sensitivities toward different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.
Topics: Humans; Multiple Myeloma; Antigenic Drift and Shift; DNA Copy Number Variations; Receptors, Chimeric Antigen; Neoplasm Recurrence, Local; Immunotherapy; Antibodies; Membrane Proteins
PubMed: 37653344
DOI: 10.1038/s41591-023-02491-5 -
British Journal of Haematology Oct 2017Approximately 0·2-1% of routine RhD blood typings result in a "serological weak D phenotype." For more than 50 years, serological weak D phenotypes have been managed... (Review)
Review
Approximately 0·2-1% of routine RhD blood typings result in a "serological weak D phenotype." For more than 50 years, serological weak D phenotypes have been managed by policies to protect RhD-negative women of child-bearing potential from exposure to weak D antigens. Typically, blood donors with a serological weak D phenotype have been managed as RhD-positive, in contrast to transfusion recipients and pregnant women, who have been managed as RhD-negative. Most serological weak D phenotypes in Caucasians express molecularly defined weak D types 1, 2 or 3 and can be managed safely as RhD-positive, eliminating unnecessary injections of Rh immune globulin and conserving limited supplies of RhD-negative RBCs. If laboratories in the UK, Ireland and other European countries validated the use of potent anti-D reagents to result in weak D types 1, 2 and 3 typing initially as RhD-positive, such laboratory results would not require further testing. When serological weak D phenotypes are detected, laboratories should complete RhD testing by determining RHD genotypes (internally or by referral). Individuals with a serological weak D phenotype should be managed as RhD-positive or RhD-negative, according to their RHD genotype.
Topics: Amino Acid Substitution; Antigenic Variation; Blood Grouping and Crossmatching; Blood Transfusion; Cost-Benefit Analysis; Female; Gene Expression; Genotype; Humans; Isoantibodies; Mutation; Phenotype; Practice Guidelines as Topic; Pregnancy; Prevalence; Rh-Hr Blood-Group System; Serologic Tests
PubMed: 28508413
DOI: 10.1111/bjh.14757 -
Blood Dec 2022Substantial numbers of B cell leukemia and lymphoma patients relapse due to antigen loss or heterogeneity after anti-CD19 chimeric antigen receptor (CAR) T cell...
Substantial numbers of B cell leukemia and lymphoma patients relapse due to antigen loss or heterogeneity after anti-CD19 chimeric antigen receptor (CAR) T cell therapy. To overcome antigen escape and address antigen heterogeneity, we engineered induced pluripotent stem cell-derived NK cells to express both an NK cell-optimized anti-CD19 CAR for direct targeting and a high affinity, non-cleavable CD16 to augment antibody-dependent cellular cytotoxicity. In addition, we introduced a membrane-bound IL-15/IL-15R fusion protein to promote in vivo persistence. These engineered cells, termed iDuo NK cells, displayed robust CAR-mediated cytotoxic activity that could be further enhanced with therapeutic antibodies targeting B cell malignancies. In multiple in vitro and xenogeneic adoptive transfer models, iDuo NK cells exhibited robust anti-lymphoma activity. Furthermore, iDuo NK cells effectively eliminated both CD19+ and CD19- lymphoma cells and displayed a unique propensity for targeting malignant cells over healthy cells that expressed CD19, features not achievable with anti-CAR19 T cells. iDuo NK cells combined with therapeutic antibodies represent a promising approach to prevent relapse due to antigen loss and tumor heterogeneity in patients with B cell malignancies.
Topics: Humans; Antigenic Drift and Shift; Leukemia; Killer Cells, Natural; Neoplasms
PubMed: 35917442
DOI: 10.1182/blood.2021015184 -
Immunity Dec 2021Antigenic drift refers to the evolutionary accumulation of amino acid substitutions in viral proteins selected by host adaptive immune systems as the virus circulates in... (Review)
Review
Antigenic drift refers to the evolutionary accumulation of amino acid substitutions in viral proteins selected by host adaptive immune systems as the virus circulates in a population. Antigenic drift can substantially limit the duration of immunity conferred by infection and vaccination. Here, I explain the factors contributing to the rapid antigenic drift of the SARS-CoV-2 spike protein and receptor proteins of other viruses and discuss the implications for SARS-CoV-2 evolution and immunity.
Topics: Adaptive Immunity; Animals; Antigenic Drift and Shift; Biological Evolution; COVID-19; Host-Pathogen Interactions; Humans; Mutation; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Vaccination
PubMed: 34910934
DOI: 10.1016/j.immuni.2021.11.016 -
Signal Transduction and Targeted Therapy Dec 2023Chimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical response in treating both hematologic malignancies and solid tumors. Although instances of rapid...
Chimeric antigen receptor (CAR) T-cell therapy has demonstrated clinical response in treating both hematologic malignancies and solid tumors. Although instances of rapid tumor remissions have been observed in animal models and clinical trials, tumor relapses occur with multiple therapeutic resistance mechanisms. Furthermore, while the mechanisms underlying the long-term therapeutic resistance are well-known, short-term adaptation remains less understood. However, more views shed light on short-term adaptation and hold that it provides an opportunity window for long-term resistance. In this study, we explore a previously unreported mechanism in which tumor cells employ trogocytosis to acquire CAR molecules from CAR-T cells, a reversal of previously documented processes. This mechanism results in the depletion of CAR molecules and subsequent CAR-T cell dysfunction, also leading to short-term antigen loss and antigen masking. Such type of intercellular communication is independent of CAR downstream signaling, CAR-T cell condition, target antigen, and tumor cell type. However, it is mainly dependent on antigen density and CAR sensitivity, and is associated with tumor cell cholesterol metabolism. Partial mitigation of this trogocytosis-induced CAR molecule transfer can be achieved by adaptively administering CAR-T cells with antigen density-individualized CAR sensitivities. Together, our study reveals a dynamic process of CAR molecule transfer and refining the framework of clinical CAR-T therapy for solid tumors.
Topics: Animals; Receptors, Antigen, T-Cell; T-Lymphocytes; Antigenic Drift and Shift; Trogocytosis; Neoplasms
PubMed: 38143263
DOI: 10.1038/s41392-023-01708-w -
Advances in Experimental Medicine and... 2017Microbes that infect other organisms encounter host immune responses, and must overcome or evade innate and adaptive immune responses to successfully establish... (Review)
Review
Microbes that infect other organisms encounter host immune responses, and must overcome or evade innate and adaptive immune responses to successfully establish infection. Highly successful microbial pathogens, including M. tuberculosis, are able to evade adaptive immune responses (mediated by antibodies and/or T lymphocytes) and thereby establish long-term chronic infection. One mechanism that diverse pathogens use to evade adaptive immunity is antigenic variation, in which structural variants emerge that alter recognition by established immune responses and allow those pathogens to persist and/or to infect previously-immune hosts. Despite the wide use of antigenic variation by diverse pathogens, this mechanism appears to be infrequent in M. tuberculosis, as indicated by findings that known and predicted human T cell epitopes in this organism are highly conserved, although there are exceptions. These findings have implications for diagnostic tests that are based on measuring host immune responses, and for vaccine design and development.
Topics: Adaptive Immunity; Antigenic Variation; Antigens, Bacterial; Conserved Sequence; Epitopes, T-Lymphocyte; Gene Expression Regulation; Genome, Bacterial; HLA Antigens; Humans; Immune Evasion; Immunity, Innate; Mycobacterium tuberculosis; Selection, Genetic; T-Lymphocytes; Tuberculosis
PubMed: 29116635
DOI: 10.1007/978-3-319-64371-7_9 -
Journal of Molecular Biology Jul 2020Trypanosoma brucei is a kinetoplastid parasite that causes African trypanosomiasis, which is fatal if left untreated. T. brucei regularly switches its major surface... (Review)
Review
Trypanosoma brucei is a kinetoplastid parasite that causes African trypanosomiasis, which is fatal if left untreated. T. brucei regularly switches its major surface antigen, VSG, to evade the host immune responses. VSGs are exclusively expressed from subtelomeric expression sites (ESs) where VSG genes are flanked by upstream 70 bp repeats and downstream telomeric repeats. The telomere downstream of the active VSG is transcribed into a long-noncoding RNA (TERRA), which forms RNA:DNA hybrids (R-loops) with the telomeric DNA. At an elevated level, telomere R-loops cause more telomeric and subtelomeric double-strand breaks (DSBs) and increase VSG switching rate. In addition, stabilized R-loops are observed at the 70 bp repeats and immediately downstream of ES-linked VSGs in RNase H defective cells, which also have an increased amount of subtelomeric DSBs and more frequent VSG switching. Although subtelomere plasticity is expected to be beneficial to antigenic variation, severe defects in subtelomere integrity and stability increase cell lethality. Therefore, regulation of the telomere and 70 bp repeat R-loop levels is important for the balance between antigenic variation and cell fitness in T. brucei. In addition, the high level of the active ES transcription favors accumulation of R-loops at the telomere and 70 bp repeats, providing an intrinsic mechanism for local DSB formation, which is a strong inducer of VSG switching.
Topics: Antigenic Variation; Cell Plasticity; Genetic Variation; R-Loop Structures; RNA, Transfer; Telomere; Trypanosoma brucei brucei; Variant Surface Glycoproteins, Trypanosoma
PubMed: 31682833
DOI: 10.1016/j.jmb.2019.10.025