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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.


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Elevated immunosuppressive factors in head and neck squamous cell carcinoma (HNSCC) patients. Patients’ plasma was analyzed for the levels of the cytokines TGF-β1, IL-6, IL-8, IL-10, IL-1β, IFN-γ, TNF-α and the chemokines MIP-1α, MIP-1β, RANTES, and MCP-1 by cytometric bead array. (A) Heat-map representation of shed NKG2DL levels (see Figure 1), cytokine and chemokine levels as x-times median control (CO; n = 12 healthy donors) grouped according to disease stage (I–IVC). Color code: yellow = normal; orange = elevated; and red = highly elevated. (B) Quantification of chemokine and cytokine levels compared to healthy controls. Data are presented as mean ± SEM. (C) TGF-β1 plasma levels grouped according to primary vs. relapsed (left) or disease stage (right: early = stage I + II; advanced = III + IV). Statistical significance was assessed by unpaired, two-tailed Student’s t-test (B) and one-way analysis of variance (C). ns, non-significant.
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Figure 2: Elevated immunosuppressive factors in head and neck squamous cell carcinoma (HNSCC) patients. Patients’ plasma was analyzed for the levels of the cytokines TGF-β1, IL-6, IL-8, IL-10, IL-1β, IFN-γ, TNF-α and the chemokines MIP-1α, MIP-1β, RANTES, and MCP-1 by cytometric bead array. (A) Heat-map representation of shed NKG2DL levels (see Figure 1), cytokine and chemokine levels as x-times median control (CO; n = 12 healthy donors) grouped according to disease stage (I–IVC). Color code: yellow = normal; orange = elevated; and red = highly elevated. (B) Quantification of chemokine and cytokine levels compared to healthy controls. Data are presented as mean ± SEM. (C) TGF-β1 plasma levels grouped according to primary vs. relapsed (left) or disease stage (right: early = stage I + II; advanced = III + IV). Statistical significance was assessed by unpaired, two-tailed Student’s t-test (B) and one-way analysis of variance (C). ns, non-significant.

Mentions: To further assess the immune status of HNSCC patients, we analyzed the plasma levels of indicative cytokines and chemokines. Elevated plasma levels could be detected for the immunosuppressive and proinflammatory factors TGF-β1, MIP-1β, RANTES, IL-8, MCP-1, and IL-6. However, compared to the plasma levels of healthy controls, HNSCC patients showed no significant differences in the levels of IFN-γ, TNF-α, IL-10, IL-1β, and MIP-1α (Figures 2A,B). Moreover, aberrant cytokine or chemokine levels were not correlated to disease stage (Figure 2A) or primary vs. relapsed HNSCC, except for TGF-β1 showing an increase between stage I and IV (2677 vs. 5358 pg/ml) (Figure 2C).


Natural Killer Group 2D Ligand Depletion Reconstitutes Natural Killer Cell Immunosurveillance of Head and Neck Squamous Cell Carcinoma
Elevated immunosuppressive factors in head and neck squamous cell carcinoma (HNSCC) patients. Patients’ plasma was analyzed for the levels of the cytokines TGF-β1, IL-6, IL-8, IL-10, IL-1β, IFN-γ, TNF-α and the chemokines MIP-1α, MIP-1β, RANTES, and MCP-1 by cytometric bead array. (A) Heat-map representation of shed NKG2DL levels (see Figure 1), cytokine and chemokine levels as x-times median control (CO; n = 12 healthy donors) grouped according to disease stage (I–IVC). Color code: yellow = normal; orange = elevated; and red = highly elevated. (B) Quantification of chemokine and cytokine levels compared to healthy controls. Data are presented as mean ± SEM. (C) TGF-β1 plasma levels grouped according to primary vs. relapsed (left) or disease stage (right: early = stage I + II; advanced = III + IV). Statistical significance was assessed by unpaired, two-tailed Student’s t-test (B) and one-way analysis of variance (C). ns, non-significant.
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Figure 2: Elevated immunosuppressive factors in head and neck squamous cell carcinoma (HNSCC) patients. Patients’ plasma was analyzed for the levels of the cytokines TGF-β1, IL-6, IL-8, IL-10, IL-1β, IFN-γ, TNF-α and the chemokines MIP-1α, MIP-1β, RANTES, and MCP-1 by cytometric bead array. (A) Heat-map representation of shed NKG2DL levels (see Figure 1), cytokine and chemokine levels as x-times median control (CO; n = 12 healthy donors) grouped according to disease stage (I–IVC). Color code: yellow = normal; orange = elevated; and red = highly elevated. (B) Quantification of chemokine and cytokine levels compared to healthy controls. Data are presented as mean ± SEM. (C) TGF-β1 plasma levels grouped according to primary vs. relapsed (left) or disease stage (right: early = stage I + II; advanced = III + IV). Statistical significance was assessed by unpaired, two-tailed Student’s t-test (B) and one-way analysis of variance (C). ns, non-significant.
Mentions: To further assess the immune status of HNSCC patients, we analyzed the plasma levels of indicative cytokines and chemokines. Elevated plasma levels could be detected for the immunosuppressive and proinflammatory factors TGF-β1, MIP-1β, RANTES, IL-8, MCP-1, and IL-6. However, compared to the plasma levels of healthy controls, HNSCC patients showed no significant differences in the levels of IFN-γ, TNF-α, IL-10, IL-1β, and MIP-1α (Figures 2A,B). Moreover, aberrant cytokine or chemokine levels were not correlated to disease stage (Figure 2A) or primary vs. relapsed HNSCC, except for TGF-β1 showing an increase between stage I and IV (2677 vs. 5358 pg/ml) (Figure 2C).

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