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Natural Killer Group 2D Ligand Depletion Reconstitutes Natural Killer Cell Immunosurveillance of Head and Neck Squamous Cell Carcinoma

View Article: PubMed Central - PubMed

ABSTRACT

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous and aggressive tumor originating from the epithelial lining of the upper aero-digestive tract accounting for 300,000 annual deaths worldwide due to failure of current therapies. The natural killer group 2D (NKG2D) receptors on natural killer (NK) cells and several T cell subsets play an important role for immunosurveillance of HNSCC and are thus targeted by tumor immune evasion strategies in particular by shedding of various NKG2D ligands (NKG2DLs). Based on plasma and tumor samples of 44 HNSCC patients, we found that despite compositional heterogeneity the total plasma level of NKG2DLs correlates with NK cell inhibition and disease progression. Strikingly, based on tumor spheroids and primary tumors of HNSCC patients, we found that NK cells failed to infiltrate HNSCC tumors in the presence of high levels of NKG2DLs, demonstrating a novel mechanism of NKG2DL-dependent tumor immune escape. Therefore, the diagnostic acquisition of the plasma level of all NKG2DLs might be instrumental for prognosis and to decipher a patient cohort, which could benefit from restoration of NKG2D-dependent tumor immunosurveillance. Along these lines, we could show that removal of shed NKG2DLs (sNKG2DLs) from HNSCC patients’ plasma restored NK cell function in vitro and in individual patients following surgical removal of the primary tumor. In order to translate these findings into a therapeutic setting, we performed a proof-of-concept study to test the efficacy of adsorption apheresis of sNKG2DLs from plasma after infusion of human MICA in rhesus monkeys. Complete removal of MICA was achieved after three plasma volume exchanges. Therefore, we propose adsorption apheresis of sNKG2DLs as a future preconditioning strategy to improve the efficacy of autologous and adoptively transferred immune cells in cellular cancer immunotherapy.

No MeSH data available.


Related in: MedlinePlus

Disease stage-dependent increase of shed NKG2DL (sNKG2DL) levels. (A) Levels of sNKG2DLs in plasma of head and neck squamous cell carcinoma (HNSCC) patients (n‚ÄČ=‚ÄČ44) compared to age-matched healthy donors (n‚ÄČ=‚ÄČ12) quantified by ELISA. (B) Cumulative sNKG2DL levels (sum of sMICA/B and sULBP1‚Äď3) grouped according to disease stage (left: early‚ÄČ=‚ÄČstage I‚ÄČ+‚ÄČII; advanced‚ÄČ=‚ÄČIII‚ÄČ+‚ÄČIV) or primary vs. relapsed HNSCC (right). (C) Plasma levels of individual sNKG2DLs grouped according to disease stage (early‚ÄČ=‚ÄČstage I‚ÄČ+‚ÄČII; advanced‚ÄČ=‚ÄČIII‚ÄČ+‚ÄČIV). Data are presented as mean‚ÄȬĪ‚ÄČSEM of representative experiments. Statistical significance was assessed by unpaired, two-tailed Student‚Äôs t-test (A) and one-way analysis of variance (B,C). ns, non-significant.
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Figure 1: Disease stage-dependent increase of shed NKG2DL (sNKG2DL) levels. (A) Levels of sNKG2DLs in plasma of head and neck squamous cell carcinoma (HNSCC) patients (n‚ÄČ=‚ÄČ44) compared to age-matched healthy donors (n‚ÄČ=‚ÄČ12) quantified by ELISA. (B) Cumulative sNKG2DL levels (sum of sMICA/B and sULBP1‚Äď3) grouped according to disease stage (left: early‚ÄČ=‚ÄČstage I‚ÄČ+‚ÄČII; advanced‚ÄČ=‚ÄČIII‚ÄČ+‚ÄČIV) or primary vs. relapsed HNSCC (right). (C) Plasma levels of individual sNKG2DLs grouped according to disease stage (early‚ÄČ=‚ÄČstage I‚ÄČ+‚ÄČII; advanced‚ÄČ=‚ÄČIII‚ÄČ+‚ÄČIV). Data are presented as mean‚ÄȬĪ‚ÄČSEM of representative experiments. Statistical significance was assessed by unpaired, two-tailed Student‚Äôs t-test (A) and one-way analysis of variance (B,C). ns, non-significant.

Mentions: Significantly elevated levels of individual sNKG2DLs were detected in patients‚Äô plasma when compared to those observed in the plasma of 12 age-matched healthy donors (Figure 1A). Moreover, the burden of sNKG2DLs in patients with advanced disease vs. healthy donors was significantly increased, whereas no significant difference between primary and relapsed HNSCC was observed (Figure 1B). Comparison of treatment na√Įve patients with patients currently under palliative chemo- or radiotherapy or after tumor resection showed a therapy induced reduction of sNKG2DL levels (Figure S1A in Supplementary Material). Notably, sNKG2D ligands were found to peak in the plasma of patients with advanced disease (Figure 1C), suggesting that the total level of sNKG2DLs represents an important clinical parameter (Figure S1B in Supplementary Material).


Natural Killer Group 2D Ligand Depletion Reconstitutes Natural Killer Cell Immunosurveillance of Head and Neck Squamous Cell Carcinoma
Disease stage-dependent increase of shed NKG2DL (sNKG2DL) levels. (A) Levels of sNKG2DLs in plasma of head and neck squamous cell carcinoma (HNSCC) patients (n‚ÄČ=‚ÄČ44) compared to age-matched healthy donors (n‚ÄČ=‚ÄČ12) quantified by ELISA. (B) Cumulative sNKG2DL levels (sum of sMICA/B and sULBP1‚Äď3) grouped according to disease stage (left: early‚ÄČ=‚ÄČstage I‚ÄČ+‚ÄČII; advanced‚ÄČ=‚ÄČIII‚ÄČ+‚ÄČIV) or primary vs. relapsed HNSCC (right). (C) Plasma levels of individual sNKG2DLs grouped according to disease stage (early‚ÄČ=‚ÄČstage I‚ÄČ+‚ÄČII; advanced‚ÄČ=‚ÄČIII‚ÄČ+‚ÄČIV). Data are presented as mean‚ÄȬĪ‚ÄČSEM of representative experiments. Statistical significance was assessed by unpaired, two-tailed Student‚Äôs t-test (A) and one-way analysis of variance (B,C). ns, non-significant.
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Related In: Results  -  Collection

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Figure 1: Disease stage-dependent increase of shed NKG2DL (sNKG2DL) levels. (A) Levels of sNKG2DLs in plasma of head and neck squamous cell carcinoma (HNSCC) patients (n‚ÄČ=‚ÄČ44) compared to age-matched healthy donors (n‚ÄČ=‚ÄČ12) quantified by ELISA. (B) Cumulative sNKG2DL levels (sum of sMICA/B and sULBP1‚Äď3) grouped according to disease stage (left: early‚ÄČ=‚ÄČstage I‚ÄČ+‚ÄČII; advanced‚ÄČ=‚ÄČIII‚ÄČ+‚ÄČIV) or primary vs. relapsed HNSCC (right). (C) Plasma levels of individual sNKG2DLs grouped according to disease stage (early‚ÄČ=‚ÄČstage I‚ÄČ+‚ÄČII; advanced‚ÄČ=‚ÄČIII‚ÄČ+‚ÄČIV). Data are presented as mean‚ÄȬĪ‚ÄČSEM of representative experiments. Statistical significance was assessed by unpaired, two-tailed Student‚Äôs t-test (A) and one-way analysis of variance (B,C). ns, non-significant.
Mentions: Significantly elevated levels of individual sNKG2DLs were detected in patients‚Äô plasma when compared to those observed in the plasma of 12 age-matched healthy donors (Figure 1A). Moreover, the burden of sNKG2DLs in patients with advanced disease vs. healthy donors was significantly increased, whereas no significant difference between primary and relapsed HNSCC was observed (Figure 1B). Comparison of treatment na√Įve patients with patients currently under palliative chemo- or radiotherapy or after tumor resection showed a therapy induced reduction of sNKG2DL levels (Figure S1A in Supplementary Material). Notably, sNKG2D ligands were found to peak in the plasma of patients with advanced disease (Figure 1C), suggesting that the total level of sNKG2DLs represents an important clinical parameter (Figure S1B in Supplementary Material).

View Article: PubMed Central - PubMed

ABSTRACT

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous and aggressive tumor originating from the epithelial lining of the upper aero-digestive tract accounting for 300,000 annual deaths worldwide due to failure of current therapies. The natural killer group 2D (NKG2D) receptors on natural killer (NK) cells and several T cell subsets play an important role for immunosurveillance of HNSCC and are thus targeted by tumor immune evasion strategies in particular by shedding of various NKG2D ligands (NKG2DLs). Based on plasma and tumor samples of 44 HNSCC patients, we found that despite compositional heterogeneity the total plasma level of NKG2DLs correlates with NK cell inhibition and disease progression. Strikingly, based on tumor spheroids and primary tumors of HNSCC patients, we found that NK cells failed to infiltrate HNSCC tumors in the presence of high levels of NKG2DLs, demonstrating a novel mechanism of NKG2DL-dependent tumor immune escape. Therefore, the diagnostic acquisition of the plasma level of all NKG2DLs might be instrumental for prognosis and to decipher a patient cohort, which could benefit from restoration of NKG2D-dependent tumor immunosurveillance. Along these lines, we could show that removal of shed NKG2DLs (sNKG2DLs) from HNSCC patients’ plasma restored NK cell function in vitro and in individual patients following surgical removal of the primary tumor. In order to translate these findings into a therapeutic setting, we performed a proof-of-concept study to test the efficacy of adsorption apheresis of sNKG2DLs from plasma after infusion of human MICA in rhesus monkeys. Complete removal of MICA was achieved after three plasma volume exchanges. Therefore, we propose adsorption apheresis of sNKG2DLs as a future preconditioning strategy to improve the efficacy of autologous and adoptively transferred immune cells in cellular cancer immunotherapy.

No MeSH data available.


Related in: MedlinePlus