Immunological ignorance is an enabling feature of the oligo-clonal T cell response to melanoma neoantigens

The impact of intratumoral heterogeneity (ITH) and the resultant neoantigen landscape on T cell immunity are poorly understood. ITH is a widely recognized feature of solid tumors and poses distinct challenges related to the development of effective therapeutic strategies, including cancer neoantigen vaccines. Here, we performed deep targeted DNA sequencing of multiple metastases from melanoma patients and observed ubiquitous sharing of clonal and subclonal single nucleotide variants (SNVs) encoding putative HLA class I-restricted neoantigen epitopes. However, spontaneous antitumor CD8+ T cell immunity in peripheral blood and tumors was restricted to a few clonal neoantigens featuring an oligo-/monoclonal T cell-receptor (TCR) repertoire. Moreover, in various tumors of the 4 patients examined, no neoantigen-specific TCR clonotypes were identified despite clonal neoantigen expression. Mature dendritic cell (mDC) vaccination with tumor-encoded amino acid-substituted (AAS) peptides revealed diverse neoantigen-specific CD8+ T responses, each composed of multiple TCR clonotypes. Isolation of T cell clones by limiting dilution from tumor-infiltrating lymphocytes (TILs) permitted functional validation regarding neoantigen specificity. Gene transfer of TCRαβ heterodimers specific for clonal neoantigens confirmed correct TCR clonotype assignments based on high-throughput TCRBV CDR3 sequencing. Our findings implicate immunological ignorance of clonal neoantigens as the basis for ineffective T cell immunity to melanoma and support the concept that therapeutic vaccination, as an adjunct to checkpoint inhibitor treatment, is required to increase the breadth and diversity of neoantigen-specific CD8+ T cells.

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Antigen Selection for Enhanced Affinity T-Cell Receptor–Based Cancer Therapies

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057116637837 ◽

2016 ◽

Vol 21 (8) ◽

pp. 769-785 ◽

Cited By ~ 8

Author(s):

Emma S. Hickman ◽

Martine E. Lomax ◽

Bent K. Jakobsen

Keyword(s):

T Cell ◽

Cancer Immunotherapy ◽

De Novo ◽

Cell Receptor ◽

T Cell Response ◽

Adoptive Cell Transfer ◽

Cytotoxic T Cell ◽

Discovery Process ◽

Cancer Antigens ◽

The Impact

Evidence of adaptive immune responses in the prevention of cancer has been accumulating for decades. Spontaneous T-cell responses occur in multiple indications, bringing the study of de novo expressed cancer antigens to the fore and highlighting their potential as targets for cancer immunotherapy. Circumventing the immune-suppressive mechanisms that maintain tumor tolerance and driving an antitumor cytotoxic T-cell response in cancer patients may eradicate the tumor or block disease progression. Multiple strategies are being pursued to harness the cytotoxic potential of T cells clinically. Highly promising results are now emerging. The focus of this review is the target discovery process for cancer immune therapeutics based on affinity-matured T-cell receptors (TCRs). Target cancer antigens in the context of adoptive cell transfer technologies and soluble biologic agents are discussed. To appreciate the impact of TCR-based technology and understand the TCR discovery process, it is necessary to understand key differences between TCR-based therapy and other immunotherapy approaches. The review first summarizes key advances in the cancer immunotherapy field and then discusses the opportunities that TCR technology provides. The nature and breadth of molecular targets that are tractable to this approach are discussed, together with the challenges associated with finding them.

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T-cell receptor transfer for boosting HIV-1-specific T-cell immunity in HIV-1-infected patients

AIDS ◽

10.1097/qad.0000000000001176 ◽

2016 ◽

Vol 30 (14) ◽

pp. 2149-2158 ◽

Cited By ~ 2

Author(s):

Christiane Mummert ◽

Christian Hofmann ◽

Angela G. Hückelhoven ◽

Silke Bergmann ◽

Sandra M. Mueller-Schmucker ◽

...

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

T Cell Immunity ◽

Cell Immunity ◽

Hiv 1

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The immune battlefield: The impact of inflammatory cytokines on CD8+ T-cell immunity

PLoS Pathogens ◽

10.1371/journal.ppat.1006618 ◽

2017 ◽

Vol 13 (10) ◽

pp. e1006618 ◽

Cited By ~ 11

Author(s):

Stephanie A. Condotta ◽

Martin J. Richer

Keyword(s):

T Cell ◽

Inflammatory Cytokines ◽

Cd8 T Cell ◽

T Cell Immunity ◽

Cell Immunity ◽

The Impact

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Coinfection with Human Cytomegalovirus Genetic Variants in Transplant Recipients and Its Impact on Antiviral T Cell Immune Reconstitution

Journal of Virology ◽

10.1128/jvi.00297-16 ◽

2016 ◽

Vol 90 (16) ◽

pp. 7497-7507 ◽

Cited By ~ 5

Author(s):

Corey Smith ◽

Rebekah M. Brennan ◽

Siok-Keen Tey ◽

Mark J. Smyth ◽

Scott R. Burrows ◽

...

Keyword(s):

T Cell ◽

Human Cytomegalovirus ◽

Genetic Variants ◽

Immune Reconstitution ◽

Hla Class I ◽

T Cell Immunity ◽

Transplant Recipients ◽

Hematopoietic Stem ◽

Cell Responses ◽

Cell Immunity

ABSTRACTReconstitution of T cell immunity is absolutely critical for the effective control of virus-associated infectious complications in hematopoietic stem cell transplant (HSCT) recipients. Coinfection with genetic variants of human cytomegalovirus (CMV) in transplant recipients has been linked to clinical disease manifestation; however, how these genetic variants impact T cell immune reconstitution remains poorly understood. In this study, we have evaluated dynamic changes in the emergence of genetic variants of CMV in HSCT recipients and correlated these changes with reconstitution of antiviral T cell responses. In an analysis of single nucleotide polymorphisms within sequences encoding HLA class I-restricted CMV epitopes from the immediate early 1 gene of CMV, coinfection with genetically distinct variants of CMV was detected in 52% of patients. However, in spite of exposure to multiple viral variants, the T cell responses in these patients were preferentially directed to a limited repertoire of HLA class I-restricted CMV epitopes, either conserved, variant, or cross-reactive. More importantly, we also demonstrate that long-term control of CMV infection after HSCT is primarily mediated through the efficient induction of stable antiviral T cell immunity irrespective of the nature of the antigenic target. These observations provide important insights for the future design of antiviral T cell-based immunotherapeutic strategies for transplant recipients, emphasizing the critical impact of robust immune reconstitution on efficient control of viral infection.IMPORTANCEInfection and disease caused by human cytomegalovirus (CMV) remain a significant burden in patients undergoing hematopoietic stem cell transplantation (HSCT). The establishment of efficient immunological control, primarily mediated by cytotoxic T cells, plays a critical role in preventing CMV-associated disease in transplant recipients. Recent studies have also begun to investigate the impact genetic variation in CMV has upon disease outcome in transplant recipients. In this study, we sought to investigate the role T cell immunity plays in recognizing and controlling genetic variants of CMV. We demonstrate that while a significant proportion of HSCT recipients may be exposed to multiple genetic variants of CMV, this does not necessarily lead to immune control mediated via recognition of this genetic variation. Rather, immune control is associated with the efficient establishment of a stable immune response predominantly directed against immunodominant conserved T cell epitopes.

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Lack of CD4+ T Cells Does Not Affect Induction of CD8+ T-Cell Immunity against Encephalitozoon cuniculi Infection

Infection and Immunity ◽

10.1128/iai.68.11.6223-6232.2000 ◽

2000 ◽

Vol 68 (11) ◽

pp. 6223-6232 ◽

Cited By ~ 39

Author(s):

Magali Moretto ◽

Lori Casciotti ◽

Brigit Durell ◽

Imtiaz A. Khan

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

T Cell Response ◽

T Cell Immunity ◽

Cell Mediated Immunity ◽

Wild Type ◽

Encephalitozoon Cuniculi ◽

Cell Immunity ◽

Mouse Tissues

ABSTRACT Cell-mediated immunity has been reported to play an important role in defense against Encephalitozoon cuniculi infection. Previous studies from our laboratory have underlined the importance of cytotoxic CD8+ T lymphocytes (CTL) in survival of mice infected with E. cuniculi. In the present study, immune response against E. cuniculi infection in CD4+T-cell-deficient mice was evaluated. Similar to resistant wild-type animals, CD4−/− mice were able to resolve E. cuniculi infection even at a very high challenge dose (5 × 107 spores/mouse). Tissues from infected CD4−/− mice did not exhibit higher parasite loads in comparison to the parental wild-type mice. Conversely, at day 21 postinfection, susceptible CD8−/− mice had 1014 times more parasites in the liver compared to control wild-type mice. Induction of the CD8+ T-cell response in CD4−/− mice against E. cuniculi infection was studied. Interestingly, a normal antigen-specific CD8+T-cell response to E. cuniculi infection was observed in CD4−/− mice (precursor proliferation frequency, 1/2.5 × 104 versus 1/104 in wild-type controls). Lack of CD4+ T cells did not alter the magnitude of the antigen-specific CTL response (precursor CTL frequency; 1/1.4 × 104 in CD4−/− mice versus 1/3 × 104 in control mice). Adoptive transfer of immune CD8+ T cells from both CD4−/− and wild-type animals prevented the mortality in CD8−/− mice.E. cuniculi infection thus offers an example of an intracellular parasitic infection where CD8+ T-cell immunity can be induced in the absence of CD4+ T cells.

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Regulation of T-cell migration by co-stimulatory molecules

Biochemical Society Transactions ◽

10.1042/bst0351114 ◽

2007 ◽

Vol 35 (5) ◽

pp. 1114-1118 ◽

Cited By ~ 3

Author(s):

R. David ◽

F.M. Marelli-Berg

Keyword(s):

Cell Migration ◽

T Cell ◽

T Cell Receptor ◽

Antigenic Site ◽

Cell Receptor ◽

T Cell Immunity ◽

T Cell Migration ◽

Cell Immunity ◽

Essential Contribution

Migration of primed T-cells to the antigenic site is an essential event in the development of effective immunity. This process is tightly regulated in order to ensure efficient and specific responses. Most studies have focused on non-specific mediators of T-cell migration, including integrins and chemokines. However, recent studies have highlighted the key role of the T-cell receptor and co-stimulatory molecules in guiding T-cell access to antigenic tissue. Here, we review the experimental evidence for an essential contribution of co-stimulation-mediated molecular interactions regulating T-cell migration in the development of T-cell immunity and tolerance.

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Children and adults with mild COVID-19 symptoms develop memory T cell immunity to SARS-CoV-2

10.1101/2021.09.10.21263333 ◽

2021 ◽

Author(s):

Patricia Kaaijk ◽

Veronica Olivo Pimentel ◽

Maarten E. Emmelot ◽

Martien Poelen ◽

Alper Cevirgel ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

T Cell Response ◽

T Cell Immunity ◽

Immune Memory ◽

Effector Memory ◽

Longitudinal Assessment ◽

Memory T Cell ◽

Cell Immunity

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to considerable morbidity/mortality worldwide, but most infections, especially among children, have a mild course. However, it remains largely unknown whether infected children develop cellular immune memory. Methods: To determine whether a memory T cell response is being developed as an indicator for long-term immune protection, we performed a longitudinal assessment of the SARS-CoV-2-specific T cell response by IFN-γ ELISPOT and activation marker expression analyses of peripheral blood samples from children and adults with mild-to-moderate COVID-19. Results: Upon stimulation of PBMCs with heat-inactivated SARS-CoV-2 or overlapping peptides of spike (S-SARS-CoV-2) and nucleocapsid proteins, we found S-SARS-CoV-2-specific IFN-ɣ T cell responses in most infected children (83%) and all adults (100%) that were absent in unexposed controls. Frequencies of SARS-CoV-2-specific T cells were higher in infected adults, especially in those with moderate symptoms, compared to infected children. The S-SARS-CoV-2 IFN-ɣ T cell response correlated with S1-SARS-CoV-2-specific serum IgM, IgG, and IgA antibody concentrations. Predominantly, effector memory CD4+ T cells of a Th1 phenotype were activated upon exposure to SARS-CoV-2 antigens, which persisted for 4-8 weeks after symptom onset. We detected very low frequencies of SARS-CoV-2-reactive CD8+ T cells in these individuals. Conclusions: Our data indicate that an antigen-specific memory CD4+ T cell response is induced in children and adults with mild SARS-CoV-2 infection. T cell immunity induced after mild COVID-19 could contribute to protection against re-infection.

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Targeting of Cdc42 GTPase in regulatory T cells unleashes anti-tumor T cell immunity

10.1101/2021.09.23.461402 ◽

2021 ◽

Author(s):

Khalid W Kalim ◽

Jun-Qi Yang ◽

Mark Wunderlich ◽

Vishnu Modur ◽

Phuong Nguyen ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Treg Cell ◽

Cell Function ◽

Treg Cells ◽

T Cell Response ◽

T Cell Immunity ◽

Cell Plasticity ◽

Effector T Cell ◽

Cell Immunity

Regulatory T (Treg) cells play an important role in maintaining immune tolerance through inhibiting effector T cell function. In the tumor microenvironment, Treg cells are utilized by tumor cells to counteract effector T cell-mediated tumor killing. Targeting Treg cells may thus unleash the anti-tumor activity of effector T cells. While systemic depletion of Treg cells can cause excessive effector T cell responses and subsequent autoimmune diseases, controlled targeting of Treg cells may benefit cancer patients. Here we show that Treg cell-specific heterozygous deletion or pharmacological targeting of Cdc42 GTPase does not affect Treg cell numbers but induces Treg cell plasticity, leading to anti-tumor T cell immunity without detectable autoimmune reactions. Cdc42 targeting potentiates an immune checkpoint blocker anti-PD-1 antibody-mediated T cell response against mouse and human tumors. Mechanistically, Cdc42 targeting induces Treg cell plasticity and unleashes anti-tumor T cell immunity through carbonic anhydrase I-mediated pH changes. Thus, rational targeting of Cdc42 in Treg cells holds therapeutic promises in cancer immunotherapy.

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Assessment of T-cell immunity to SARS-CoV-2 in COVID-19 convalescents and vaccinated subjects, using TigraTest® SARS-CoV-2 ELISPOT kit

BIOpreparations Prevention Diagnosis Treatment ◽

10.30895/2221-996x-2021-21-3-178-192 ◽

2021 ◽

Vol 21 (3) ◽

pp. 178-192

Author(s):

D. A. Poteryaev ◽

S. G. Abbasova ◽

P. E. Ignatyeva ◽

O. M. Strizhakova ◽

S. V. Kolesnik ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Peripheral Blood ◽

Cell Response ◽

Human Peripheral Blood ◽

T Cell Response ◽

T Cell Immunity ◽

Cell Immunity

With the onset of the COVID-19 pandemic, a number of molecular-based tests have been developed to diagnose SARS-CoV-2 infection. However, numerous available serological tests lack sufficient sensitivity or specificity. They do not detect specific antibodies in a significant proportion of patients with PCR-confirmed COVID-19. There is evidence that some convalescents have a relatively short-lived humoral immunity. In contrast, a number of publications have shown that T-cell response to human coronaviruses, including SARS-CoV-1, MERS, and SARS-CoV-2, can be strong and long-term. Assessment of T-cell immunity to SARS-CoV-2 is important not only for stratification of risks and identification of potentially protected populations with immunity acquired as a result of previous infection, but also for determining immunogenicity and potential efficacy of vaccines under development. The existing methods of quantitative or semi-quantitative assessment of specific T-cell response are mainly used in scientific research and are not standardised. The aim of the study was to develop and verify experimentally a test kit to be used in a standardised procedure for in vitro determination of T-cells specific to SARS-CoV-2 antigens, in human peripheral blood. Materials and methods: the TigraTest® SARS-CoV-2 kit developed by GENERIUM, which determines the number of T-cells secreting interferon gamma in vitro, was tested in the study. Samples of venous blood of volunteers from three different groups were analysed in the study: presumably healthy volunteers; COVID-19 convalescents; individuals vaccinated against SARS-CoV-2. Results: the authors developed the TigraTest® SARS-CoV-2 kit for in vitro determination of T-cells specific to SARS-CoV-2 antigens in human peripheral blood, demonstrated its specificity and performed preliminary assessment of its sensitivity. The study analysed the range and magnitude of the T-cell response in convalescent and vaccinated individuals. A pronounced T-cell response was also shown in some individuals with no symptoms or with unconfirmed diagnosis. It was discovered that the mean T-cell response to peptides of the spike protein (S-protein) was higher in the vaccinated individuals than in the convalescent patients. A correlation was determined between the severity of the disease and the level of T-cell response. Specific contributions of various groups of antigens to the T-cell response after COVID-19 infection were also determined. Conclusions: the TigraTest® SARS-CoV-2 kit is a specific and sensitive tool for the assessment of T-cell immunity to the SARS-CoV-2 virus, which can also be used for vaccinated individuals. The kit may be used in clinical practice for comprehensive assessment of immunity to SARS-CoV-2.

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91. Differential Impact of Cytomegalovirus (CMV) Donor (D) Serostatus on Rates and Kinetics of CMV Viremia among CMV Seropositive Recipients (R+) of Ex vivo T-cell Depleted (TCD) and Unmodified (CONV) Hematopoietic Cell Transplants (HCT)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz359.015 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S7-S7

Author(s):

Anat Stern ◽

Yiqi Su ◽

Jiaqi Fang ◽

Miguel Perales ◽

Molly Maloy ◽

...

Keyword(s):

T Cell ◽

Ex Vivo ◽

Hematologic Malignancies ◽

T Cell Immunity ◽

Similar Frequency ◽

Viral Loads ◽

Cell Immunity ◽

Cell Transplants ◽

The Impact ◽

Kinetics Of

Abstract Background In unmodified (CONV) HCT, CMV donor seropositivity (D+) conveys partial protection against CMV disease mediated by the transfer of donor CMV T-cell immunity through the allograft. Ex vivo T-cell depletion by CD34 selection affords a stringent depletion of donor T cells, thus transfer of donor T-cell immunity to CMV would be negligible. We evaluate the impact of CMV D serostatus on rates and kinetics of CMV viremia by Day (D)100 post-HCT in a contemporary cohort of CONV and TCD recipients from a single center. Methods A retrospective cohort study of R+ adult recipients of first peripheral blood or marrow HCT for hematologic malignancies (excluding multiple myeloma) from June 2010 to December 2017 at MSKCC. Routine CMV monitoring by a quantitative PCR assay occurred weekly from D14 through D100. Patients were treated preemptively. CMV viral burden was assessed as the time-averaged area under the viremia curve over 100 days from HCT (AAUC) calculated as the sum of the area of trapezoids of AUC viral loads divided by the number of weeks of follow-up viremia. The median AAUC for all patients with CMV reactivation (AAUC50) was used to classify patients as CMV controllers (AAUC ≤ AAUC50) or noncontrollers (AAUC >AAUC50). Results Of 509 R+, 290 (57%) patients received CONV and 219 (43%) TCD HCT; from 300 (59%) D+ and 209 (41%) D− donors. In CONV, CMV viremia occurred with similar frequency in D+ (65%) and D− (62%), P = 0.6. In contrast, in TCD, CMV viremia occurred more frequently in D+ compared with D− (83% vs. 71%, P = 0.03). Among CONV, D+ was associated with lower CMV burden (median AAUC) compared with D− (0.791 vs. 1.13, respectively, P = 0.0004). In contrast, in TCD, AAUC was similar between D− and D+ (1.19 vs. 1.35; P = 0.86). Among CONV with CMV viremia, D− were more likely to be noncontrollers compared with D+ (56% vs. 31%, respectively, P = 0.001). In contrast, among TCD with CMV viremia the proportion of noncontrollers was similar between D− and D+ (61% vs. 60%, respectively; P = 1). Conclusion Donor CMV serostatus has a differential effect on rates and kinetics of CMV viremia in R+ TCD and CONV HCT recipients. D+ is associated with less CMV viremia and less CMV burden in CONV but not in TCD. Our findings, if confirmed, have implications for donor selection algorithms. Disclosures All Authors: No reported Disclosures.

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