Down-Regulation of HLA Class I Antigen Processing Molecules: An Immune Escape Mechanism of Renal Cell Carcinoma?

Atkins, Derek; Ferrone, Soldano; Schmahl, Gerd E.; Störkel, Stefan; Seliger, Barbara

doi:10.1097/01.ju.0000094807.95420.fe

Cited by 89 publications

(75 citation statements)

References 18 publications

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“…Lower hTERT activity and lower HLA-A*0201 expression by LNCaP cells could thus account for the lesser cytolysis. This result is consistent with findings indicating that tumors can escape immune surveillance by down-regulating HLA (58)(59)(60) or antigen (39,61). It is also notable that the hematologic tumor cells (K562-A2 and SKLY-18) were lysed more effectively than the solid tumors (SK-Mel-29 and LNCaP).…”

Section: Discussionsupporting

confidence: 81%

“…The p865-stimulated T cells exhibited 92% lytic activity of T2 cells pulsed with the p865 peptide, whereas 14% killing was noted of T2 cells loaded with a control HLA-A*0201-restricted peptide for the Wilms' tumor gene (RMFPNAPYL) at an E:T ratio of 50:1. T cells from the same donor stimulated by AAPC A*0201flu containing the minigene for the HLA-A*0201-specific, influenza matrix proteinderived peptide [58][59][60][61][62][63][64][65][66] (GILGFVFTL) generated 4% killing of T2 cells pulsed with p865 peptide at an E:T ratio of 50:1.…”

Section: Resultsmentioning

confidence: 99%

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Artificial Antigen-Presenting Cells Transduced with Telomerase Efficiently Expand Epitope-Specific, Human Leukocyte Antigen–Restricted Cytotoxic T Cells

Dupont

Latouche

et al. 2005

Cancer Research

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Human telomerase reverse transcriptase (hTERT) is overexpressed in most human tumors, making it a potential target for cancer immunotherapy. hTERT-derived CTL epitopes have been identified previously, including p865 (RLVDDFLLV) and p540 (ILAKFLHWL), which are restricted by the human leukocyte antigen (HLA) class I A*0201 allele. However, it remains a major challenge to efficiently and consistently expand hTERT-specific CTLs from donor peripheral blood T lymphocytes. To bypass the need for generating conventional antigen-presenting cells (APCs) on an autologous basis, we investigated the potential ability of fibroblast-derived artificial APCs (AAPCs) to activate and expand HLA-A*0201-restricted CTLs. We show here that AAPCs stably expressing HLA-A*0201, human B 2 -microglobulin, B7.1, intercellular adhesion molecule-1, and LFA-3, together with either p540 and p865 minigenes or the full-length hTERT, effectively stimulate tumoricidal, hTERT-specific CTLs. hTERT-expressing AAPCs stimulated both p540 and p865 CTLs as shown by peptide-specific cytolysis and tetramer staining, indicating that hTERT is processed by the AAPCs and that the two peptides are presented as codominant epitopes. The level of cytotoxic activity against a panel of tumors comprising hematologic and epithelial malignancies varied, correlating overall with the level of HLA-A2 and hTERT expression by the target cell. Starting from 100 mL blood, f100 million hTERTspecific CTLs could be generated over the course of five sequential stimulations, representing an expansion of f1 Â 10 5 . Our data show that AAPCs process hTERT antigen and efficiently stimulate hTERT-specific CTLs from human peripheral blood T lymphocytes and suggest that sufficient expansion could be achieved to be clinically useful for adoptive cell therapy. (Cancer Res 2005; 65(12): 5417-27)

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Section: Discussionsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Artificial Antigen-Presenting Cells Transduced with Telomerase Efficiently Expand Epitope-Specific, Human Leukocyte Antigen–Restricted Cytotoxic T Cells

Dupont

Latouche

et al. 2005

Cancer Research

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“…A Perier et al to downregulate HLA-I and II genes (Osborne et al, 1997;Atkins et al, 2004;Zagzag et al, 2005). Abnormalities in the expression of HLA molecules altering antigen presentation may contribute to tumors evading the adaptive immune response (Seliger et al, 2000), but promote NK activation.…”

Section: Mutated Vhl Rcc Cells and Nk Cell Activationmentioning

confidence: 99%

Mutations of the von Hippel–Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma

et al. 2011

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The tumor suppressor gene von Hippel-Lindau (VHL) is involved in the development of sporadic clear-cell renal cell carcinoma (RCC). VHL interferes with angiogenesis and also controls cell adhesion and invasion. Therapies that target VHL-controlled genes are currently being evaluated in RCC patients. RCC is a immunogenic tumor and treatment with interleukin-2 (IL2) or interferon (IFN)-a results in regression in some patients. We used two renal tumor cell lines (RCC6 and RCC4) carrying VHL loss-of-function mutations to investigate the role of mutant VHL in susceptibility to natural killer (NK) cellmediated lysis. The RCC6 and RCC4 cell lines were transfected with the wild-type gene to restore the function of VHL. The presence of the gene in RCC cells downregulated hypoxia-inducible factor (HIF)-1a and subsequently decreased vascular endothelial growth factor (VEGF) production. Relative to control transfectants and parental cells, pVHL-transfected cell lines activated resting and IL2-activated NK cells less strongly, as assessed by IFNc secretion, NK degranulation and cell lysis. NKG2A, a human leukocyte antigen (HLA)-Ispecific inhibitory NK receptor, controls the lysis of tumor targets. We show that HLA-I expression in RCC-pVHL cells is stronger than that in parental and controls cells, although the expression of activating receptor NK ligands remains unchanged. Blocking NKG2A/HLA-I interactions substantially increased lysis of RCC-pVHL, but had little effect on the lysis of VHL-mutated RCC cell lines. In addition, in response to IFNa, the exponential growth of RCC-pVHL was inhibited more than that of RCC-pE cells, indicating that VHL mutations may be involved in IFNa resistance. These results indicate that a decreased expression of HLA-I molecules in mutated VHL renal tumor cells sensitizes them to NK-mediated lysis. These results suggest that combined immunotherapy with antiangiogenic drugs may be beneficial for patients with mutated VHL.

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“…[4][5][6][7][8] Furthermore, we and other groups have shown that the cytotoxic immune response can fail owing to altered antigen presentation by previous downregulation of APM components. 1,9,10 Surprisingly, little is known about the APM in haematopoietic malignancies, such as acute myeloid leukaemia (AML). Treatment of high-risk or relapsed AML patients is mainly based on the induction of a graft-versus-leukaemia effect after allogenic haematopoietic stem cell transplantation, where donor immune cells recognize minor histocompatibilty antigens on residual blasts and exert a cytotoxic response against leukaemia.…”

Section: Introductionmentioning

confidence: 99%

“…This mechanism is crucial for recognition of virally infected cells, maintenance of self-tolerance and the surveillance of newly arising tumours by the immune system. 1 The presentation of tumour antigens on MHC class I surface molecules allows cytotoxic T lymphocytes to detect and, subsequently, kill antigen-specific malignant cells. 2,3 Defects in APM have been correlated with enhanced tumour growth and malignancy in solid tumours.…”

Section: Introductionmentioning

confidence: 99%

In situ analysis of the antigen-processing machinery in acute myeloid leukaemic blasts by tissue microarray

et al. 2009

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Down-Regulation of HLA Class I Antigen Processing Molecules: An Immune Escape Mechanism of Renal Cell Carcinoma?

Abstract: HLA class I APM component abnormalities appear to represent an immune escape mechanism of RCC. This finding emphasizes the need to evaluate the integrity and expression of these molecules in patients with RCC, especially in those selected for treatment with T-cell based immunotherapy.

Cited by 89 publications

References 18 publications

Artificial Antigen-Presenting Cells Transduced with Telomerase Efficiently Expand Epitope-Specific, Human Leukocyte Antigen–Restricted Cytotoxic T Cells

Artificial Antigen-Presenting Cells Transduced with Telomerase Efficiently Expand Epitope-Specific, Human Leukocyte Antigen–Restricted Cytotoxic T Cells

Mutations of the von Hippel–Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma

In situ analysis of the antigen-processing machinery in acute myeloid leukaemic blasts by tissue microarray

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