Human leucocyte antigen class I-redirected anti-tumour CD4+ T cells require a higher T cell receptor binding affinity for optimal activity than CD8+ T cells

Tan, Mai Ping; Dolton, Garry; Gerry, Andrew B.; Brewer, Joanna E.; Bennett, Alan; Pumphrey, Nick; Jakobsen, Bent K.; Sewell, Andrew K.

doi:10.1111/cei.12828

Cited by 30 publications

(29 citation statements)

References 46 publications

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“…Polyfunctionality is a highly desirable feature of potent CD8 þ T cells, well known in infections (17), but only recently described in cancer immunity (11,27). This feature is known to correlate with antigen-sensitivity and TCR affinity for cognate antigen (18,28). We showed that polyfunctional tumorreactive CD8 þ T cells accumulate in the peripheral blood of patients treated with TILs and that individual clonotypes within the TILs persist in patient peripheral blood 6 months after treatment.…”

Section: Discussionmentioning

confidence: 72%

PD-1+ Polyfunctional T Cells Dominate the Periphery after Tumor-Infiltrating Lymphocyte Therapy for Cancer

Donia

Kjeldsen

Andersen

et al. 2017

Clinical Cancer Research

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Infusion of highly heterogeneous populations of autologous tumor-infiltrating lymphocytes (TIL) can result in tumor regression of exceptional duration. Initial tumor regression has been associated with persistence of tumor-specific TILs 1 month after infusion, but mechanisms leading to long-lived memory responses are currently unknown. Here, we studied the dynamics of bulk tumor-reactive CD8 T-cell populations in patients with metastatic melanoma following treatment with TILs. We analyzed the function and phenotype of tumor-reactive CD8 T cells contained in serial blood samples of 16 patients treated with TILs. Polyfunctional tumor-reactive CD8 T cells accumulated over time in the peripheral lymphocyte pool. Combinatorial analysis of multiple surface markers (CD57, CD27, CD45RO, PD-1, and LAG-3) showed a unique differentiation pattern of polyfunctional tumor-reactive CD8 T cells, with highly specific PD-1 upregulation early after infusion. The differentiation and functional status appeared largely stable for up to 1 year after infusion. Despite some degree of clonal diversification occurring within the bulk tumor-reactive CD8 T cells, further analyses showed that CD8 T cells specific for defined tumor antigens had similar differentiation status. We demonstrated that tumor-reactive CD8 T-cell subsets that persist after TIL therapy are mostly polyfunctional, display a stable partially differentiated phenotype, and express high levels of PD-1. These partially differentiated PD-1 polyfunctional TILs have a high capacity for persistence and may be susceptible to PD-L1/PD-L2-mediated inhibition. .

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Section: Discussionmentioning

confidence: 72%

PD-1+ Polyfunctional T Cells Dominate the Periphery after Tumor-Infiltrating Lymphocyte Therapy for Cancer

Donia

Kjeldsen

Andersen

et al. 2017

Clinical Cancer Research

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“…Polyfunctionality is a desirable feature of potent CD8 þ T cells, well known in infections (29), but only recently described in cancer immunity (11,30). This feature is known to correlate with antigen sensitivity and TCR affinity for cognate antigen (31,32), antigen concentration (33), and, partially, differentiation status (34). We recently showed that polyfunctional T cells dominate the periphery after successful TIL therapy for cancer (35).…”

Section: Polyfunctional Characterization Of Tumor-reactive Cd8 þ T Cellsmentioning

confidence: 99%

T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma—Implications for Adoptive Cell Therapy

Andersen

Westergaard

Kjeldsen

et al. 2018

Cancer Immunology Research

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expansion of large numbers of highly potent tumor-reactive T cells appears a prerequisite for effective adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TIL) as shown in metastatic melanoma (MM). We therefore sought to determine whether renal cell carcinomas (RCC) are infiltrated with tumor-reactive T cells that could be efficiently employed for adoptive transfer immunotherapy. TILs and autologous tumor cell lines (TCL) were successfully generated from 22 (92%) and 17 (77%) of 24 consecutive primary RCC specimens and compared with those generated from metastatic melanoma. Immune recognition of autologous TCLs or fresh tumor digests was observed in CD8 TILs from 82% of patients (18/22). Cytotoxicity assays confirmed the tumoricidal capacity of RCC-TILs. The overall expansion capacity of RCC-TILs was similar to MM-TILs. However, the magnitude, polyfunctionality, and ability to expand in classical expansion protocols of CD8 T-cell responses was lower compared with MM-TILs. The RCC-TILs that did react to the tumor were functional, and antigen presentation and processing of RCC tumors was similar to MM-TILs. Direct recognition of tumors with cytokine-induced overexpression of human leukocyte antigen class II was observed from CD4 T cells (6/12; 50%). Thus, TILs from primary RCC specimens could be isolated, expanded, and could recognize tumors. However, immune responses of expanded CD8 RCC-TILs were typically weaker than MM-TILs and displayed a mono-/oligofunctional pattern. The ability to select, enrich, and expand tumor-reactive polyfunctional T cells may be critical in developing effective ACT with TILs for RCC. In summary, TILs isolated from primary RCC specimens could recognize tumors. However, their immune responses were weaker than MM-TILs and displayed a mono-/oligofunctional pattern. The ability to select and expand polyfunctional T cells may improve cell therapy for RCC. .

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“…T-cell receptor (TCR) ligation to a peptide presenting HLA molecule (pHLA) is critical to the effective activation of T-cells ( 20 , 21 ). The binding affinity between the TCR and core region of the peptide coupled with the half-life of peptide-TCR interaction collectively govern the downstream effector function ( 22 , 23 ). The TCR-pHLA binding affinity confers underlying signaling cascades leading to an increased demand for the extracellular glucose needed to produce biosynthetic intermediates for proliferation in addition to cellular ATP ( 24 , 25 ).…”

Section: Introductionmentioning

confidence: 99%

Metabolic Adaptation of Human CD4+ and CD8+ T-Cells to T-Cell Receptor-Mediated Stimulation

et al. 2017

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Linking immunometabolic adaptation to T-cell function provides insight for the development of new therapeutic approaches in multiple disease settings. T-cell activation and downstream effector functions of CD4+ and CD8+ T-cells are controlled by the strength of interaction between the T-cell receptor (TCR) and peptides presented by human leukocyte antigens (pHLA). The role of TCR–pHLA interactions in modulating T-cell metabolism is unknown. Here, for the first time, we explore the relative contributions of the main metabolic pathways to functional responses in human CD4+ and CD8+ T-cells. Increased expression of hexokinase II accompanied by higher basal glycolysis is demonstrated in CD4+ T-cells; cytokine production in CD8+ T-cells is more reliant on oxidative phosphorylation. Using antigen-specific CD4+ and CD8+ T-cell clones and altered peptide ligands, we demonstrate that binding affinity tunes the underlying metabolic shift. Overall, this study provides important new insight into how metabolic pathways are controlled during antigen-specific activation of human T-cells.

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Human leucocyte antigen class I-redirected anti-tumour CD4+ T cells require a higher T cell receptor binding affinity for optimal activity than CD8+ T cells

Cited by 30 publications

References 46 publications

PD-1+ Polyfunctional T Cells Dominate the Periphery after Tumor-Infiltrating Lymphocyte Therapy for Cancer

PD-1+ Polyfunctional T Cells Dominate the Periphery after Tumor-Infiltrating Lymphocyte Therapy for Cancer

T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma—Implications for Adoptive Cell Therapy

Metabolic Adaptation of Human CD4+ and CD8+ T-Cells to T-Cell Receptor-Mediated Stimulation

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