Constant regulation for stable CD8 T‐cell functional avidity and its possible implications for cancer immunotherapy

Gilfillan, Connie B.; Hebeisen, Michael; Rufer, Nathalie

doi:10.1002/eji.202049016

Cited by 5 publications

(6 citation statements)

References 136 publications

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“…EC 50 : the concentration of peptide producing half-maximal T cell responses during in vitro functional titration assay). Since functional avidity represents a major hallmark of T cell-associated tumor clearance ( 10 ), its systematic assessment in detailed cytokine or killing assays represents a crucial readout for categorizing the tumor cell recognition capacity of distinct cytotoxic T cells.…”

Section: Introductionmentioning

confidence: 99%

“…The characteristics and binding strength of the antigenic peptide within the HLA binding groove (i.e. peptide:HLA affinity) also impacts on the biological outcome and functional avidity of T cells ( 10 , 25 , 26 ). Altered peptide variants (also referred to as mimotopes or heteroclitic peptides) with increased affinity for MHC/HLA showed superior T cell activation potential and tumor cell control than the native peptide antigen in mouse models ( 27 – 29 ), prompting their use in clinical trials ( 30 ).…”

Section: Introductionmentioning

confidence: 99%

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CD8 T cell function and cross-reactivity explored by stepwise increased peptide-HLA versus TCR affinity

Baumgaertner

Schmidt²,

Costa-Nunes³

et al. 2022

Front. Immunol.

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Recruitment and activation of CD8 T cells occur through specific triggering of T cell receptor (TCR) by peptide-bound human leucocyte antigen (HLA) ligands. Within the generated trimeric TCR-peptide:HLA complex, the molecular binding affinities between peptide and HLA, and between TCR and peptide:HLA both impact T cell functional outcomes. However, how their individual and combined effects modulate immunogenicity and overall T cell responsiveness has not been investigated systematically. Here, we established two panels of human tumor peptide variants differing in their affinity to HLA. For precise characterization, we developed the “blue peptide assay”, an upgraded cell-based approach to measure the peptide:HLA affinity. These peptide variants were then used to investigate the cross-reactivity of tumor antigen-specific CD8 T cell clonotypes derived from blood of cancer patients after vaccination with either the native or an affinity-optimized Melan-A/MART-1 epitope, or isolated from tumor infiltrated lymph nodes (TILNs). Vaccines containing the native tumor epitope generated T cells with better functionality, and superior cross-reactivity against potential low affinity escape epitopes, as compared to T cells induced by vaccines containing an HLA affinity-optimized epitope. Comparatively, Melan-A/MART-1-specific TILN cells displayed functional and cross-reactive profiles that were heterogeneous and clonotype-dependent. Finally, we took advantage of a collection of T cells expressing affinity-optimized NY-ESO-1-specific TCRs to interrogate the individual and combined impact of peptide:HLA and TCR-pHLA affinities on overall CD8 T cell responses. We found profound and distinct effects of both biophysical parameters, with additive contributions and absence of hierarchical dominance. Altogether, the biological impact of peptide:HLA and TCR-pHLA affinities on T cell responses was carefully dissected in two antigenic systems, frequently targeted in human cancer immunotherapy. Our technology and stepwise comparison open new insights into the rational design and selection of vaccine-associated tumor-specific epitopes and highlight the functional and cross-reactivity profiles that endow T cells with best tumor control capacity.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CD8 T cell function and cross-reactivity explored by stepwise increased peptide-HLA versus TCR affinity

Baumgaertner

Schmidt²,

Costa-Nunes³

et al. 2022

Front. Immunol.

Self Cite

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“…Ag sensitivity of CD8 T cells can be assessed using direct ex vivo peptide stimulation and cytokine production. Multiple factors can affect peptide-induced cytokine production by a CD8 T cell population: CD8 T cell–intrinsic factors, the ability of tissue APCs to stimulate a T cell response, and competition between cells for interaction with APCs presenting cognate Ag ( 34 ). To assess T cell–intrinsic differences in functional avidity across tissues, we have established a methodology wherein splenocytes and tissue cells are stimulated within the same well, and the percent of each population producing IFN-γ was determined at multiple Ag concentrations.…”

Section: Resultsmentioning

confidence: 99%

“…Functional avidity is a measure of a T cell’s ability to produce cytokines in response to titrated Ag concentrations and is a function of both TCR affinity for cognate Ag and dynamic regulation ( 19 , 31 , 34 , 35 ). To investigate how the functional avidity of CD8 T cell populations generated after IAV infection was regulated independently of the variable of TCR affinity, we made use of TCR-Tg P14 cells with a fixed TCR that is specific for the epitope gp33–41, derived from LCMV, and recombinant IAV expressing the gp33 epitope (PR8-gp33).…”

Section: Resultsmentioning

confidence: 99%

Influenza-Induced CD103+ T Resident Memory Cells Exhibit Enhanced Functional Avidity over CD103− Memory T Cells in the Mediastinal Lymph Node

Crooks

Varga²,

Harty³

2022

ImmunoHorizons

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Influenza virus-specific tissue-resident memory CD8 T cells (Trms) targeting conserved viral proteins provide strain-transcending heterosubtypic immunity to infection. Trms in the lung combat reinfection through rapid cytolytic function and production of inflammatory cytokines to recruit other immune cells. Influenza-specific Trms are also generated in the lung draining mediastinal lymph node (mLN) and can provide immunity to heterologous virus infection in this tissue, although their role in combating influenza infection is less well defined. Functional avidity, a measure of T cell sensitivity to Ag stimulation, correlates with control of viral infection and may be important for immune detection of recently infected cells, when low numbers of surface peptide-MHC complexes are displayed. However, the functional avidity of influenza-specific Trms has not been previously compared with that of other memory CD8 T cell subsets. In this article, a methodology is presented to compare the functional avidity of CD8 T cell subsets across murine tissues, with a focus on influenza-specific mLNs compared with splenic CD8 T cells, by stimulating both populations in the same well to account for CD8 T cell-extrinsic variables. The functional avidity of influenza-specific mLN effector CD8 T cells is slightly increased relative to splenic effector CD8 T cells. However, CD103 + mLN Trms display increased functional avidity compared with splenic memory CD8 T cells and CD103 À memory CD8 T cells within the mLN. In contrast, lung-derived CD103 + Trms did not exhibit enhanced functional avidity. mLN CD103 + Trms also exhibit increased TCR expression, providing a potential mechanism for their enhanced functional avidity. ImmunoHorizons, 2022, 6: 705-715.

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“…For these cells to participate, they need the threshold for activation to be manipulated in their favor (Figure 3). To trigger full activation of CD8 T cells, both the amount of presented antigen and the affinity of the TCR for the antigen-MHC combination matter [83,84]. This interaction is helped by innate adjuvants, which can increase antigen processing and presentation and upregulate costimulatory molecules such as CD80 and CD86 [85][86][87][88][89] (Figure 3).…”

Section: Therapeutic Interventions To Bring New Responses To the Tumormentioning

confidence: 99%

Development and therapeutic manipulation of the head and neck cancer tumor environment to improve clinical outcomes

Duhen

Gough

Leidner

et al. 2022

Front. Oral. Health

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The clinical response to cancer therapies involves the complex interplay between the systemic, tumoral, and stromal immune response as well as the direct impact of treatments on cancer cells. Each individual's immunological and cancer histories are different, and their carcinogen exposures may differ. This means that even though two patients with oral tumors may carry an identical mutation in TP53, they are likely to have different pre-existing immune responses to their tumors. These differences may arise due to their distinct accessory mutations, genetic backgrounds, and may relate to clinical factors including previous chemotherapy exposure and concurrent medical comorbidities. In isolation, their cancer cells may respond similarly to cancer therapy, but due to their baseline variability in pre-existing immune responses, patients can have different responses to identical therapies. In this review we discuss how the immune environment of tumors develops, the critical immune cell populations in advanced cancers, and how immune interventions can manipulate the immune environment of patients with pre-malignancies or advanced cancers to improve therapeutic outcomes.

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Constant regulation for stable CD8 T‐cell functional avidity and its possible implications for cancer immunotherapy

Cited by 5 publications

References 136 publications

CD8 T cell function and cross-reactivity explored by stepwise increased peptide-HLA versus TCR affinity

CD8 T cell function and cross-reactivity explored by stepwise increased peptide-HLA versus TCR affinity

Influenza-Induced CD103+ T Resident Memory Cells Exhibit Enhanced Functional Avidity over CD103− Memory T Cells in the Mediastinal Lymph Node

Development and therapeutic manipulation of the head and neck cancer tumor environment to improve clinical outcomes

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