Dissecting the role of hyperthermia in natural killer cell mediated anti-tumor responses

Figures & data

Table I.  Chronological summary of studies investigating the effects of hyperthermia on NK cell function.

Year	Reference	Model	Temperature & duration	Conclusions
1982	[60]	Human: peripheral blood lymphocytes of healthy donors against K562 cells, in vitro hyperthermia	38.5–40°C, 2,4,12 hr	NK cell activity decreased with hyperthermia
1982	[46]	Human: whole body hyperthermia of patients with Ewing's sarcoma	41.8°C	Increased NK activity
1982	[61]	Human: peripheral blood lymphocytes versus K562 cells, in vitro hyperthermia	38–40°C during cytotoxicity assays	Decreased NK cell activity at 38°C and above
1983	[110]	Human: lymphocytes from healthy volunteers. NK activity measured against K562, in vitro hyperthermia	37–42°C, 3 hr	At 42°C, 90% of cytotoxic activity was lost, slight decrease in lymphocyte viability with thermal stress
1983	[111]	Human: peripheral blood NK cells from volunteers, in vitro hyperthermia	42°C, 1 hr	Viable cells, abolished NK activity
1986	[62]	Human: healthy donor peripheral blood cells against K562 cells, in vitro hyperthermia	39°C, 18 hr	Reduced NK activity
1986	[112]	Hamster: in vivo ultrasound hyperthermia on spleen	38–43°C, 8 min (500 sec)	Significant depression of NK cytotoxic activity in 4 hr, back to normal in 24 hr. Lymphophenia at 4, 8, 16 hr, recovers within 48 hr
1987	[113]	Human: PBMC, in vivo hyperthermia	39°C	NK activity was increased with elevation of core body temperature
1987	[114]	Mouse: spectrin distribution in lymphocytes, whole body hyperthermia	40.5°C, 1.5 hr	Increase in polar spectrin aggregates in splenic lymphocytes, but not in thymic lymphocytes
1988	[115]	Mouse: whole body hyperthermia, in combination with cyclophosphamide	39.5–40°C, 30 min	Higher NK activity, with hyperthermia or in combination. Prolonged lifespan is probably NK mediated
1989	[116]	Human: in vitro hyperthermia of PBMC	44°C	NK activity reduced to 4.3% after treatment
1990	[117]	Rat: in vitro hyperthermia from rat lung, peripheral blood and spleen	42.5°C, 30 min	95% inhibition of NK activity
1990	[118]	Mouse: NK activity from C3H mice, local hyperthermia	43°C, 45 min	NK activity suppressed, lowest at 2 days then significantly enhanced on day 7, counteracted with liposome encapsulated recombinant human superoxide dismutase
			41°C	NK activity announced
1991	[119]	Human: PBMC from healthy volunteers, water immersion whole body hyperthermia	39.5°C, 2 h	Number and IL2 enhanced NK cell activity was increased during hyperthermia. Elevated stress hormone levels
1991	[120]	Mouse: virally infected mice, treated with M-CSF and hyperthermia, splenic NK activity measured. Whole body microwave hyperthermia	38.8°–40.2°C	M-CSF or hyperthermia treatment alone has no effect; combination therapy restores NK activity to normal
1991	[121]	Human: PBMC, NK cytotoxic activity, in vitro hyperthermia	42°C, 30 min	40-50% decrease in NK lytic activity
			43°C, 30 min	80–90% decrease
			44°–45°C, 30 min	100% decrease, (NK cells still show recognition and binding, competitive inhibition of unheated NK cells)
			Same treatments for target cells	No effect
1991	[122]	Mouse: OK-432 (Picibanil) effects on C3Hf/Sed mice with fibrosarcoma (Fsa-II), in vivo and in vitro hyperthermia	44°C, 30 min	Thermal enhancement is eliminated with asialo-GM1. NK activity is stimulated when OK-432 is locally administered with hyperthermia
1991	[48]	Human: transrectal hyperthermia of prostate	45°C, 30 min	Significant increase in NK cytotoxic activity
1992	[123]	Rat: splenic NK cells, in vitro hyperthermia using a water bath	41°–42.5°C, 30 min	Binding of NK to targets is not affected by hyperthermia. MTOC reorientation reduced by 40%, 62–77% inhibition of NK lytic activity, lytic activity peaked at 6 hr
1993	[69]	Mouse: local microwave hyperthermia of mice with B16. F10 melanoma in combination with IL2	42°C, 30 min 43°C, 15 min	Infiltration of macrophages and NK cells observed
1993	[67]	Mouse: local microwave hyperthermia of B16. F10 melanoma in combination with IFN-β	43°C, 15 min	Tumor infiltration of NK cells with hyperthermia. Infiltration is lost with combined therapy
1993	[124]	Mouse: M-CSF and local hyperthermia treatment of B16 melanoma	43°C, 30 min twice a week for 2 weeks	Combined therapy prolonged survival, restoration of NK activity and TNF-α levels
1994	[125]	Human: effects of exercise to NK cell function	Natural body temperature increase after excercise	Acute exercise increases NK cell function, possible relation to hyperthermia. Severe exercise suppresses NK cell function through prostaglandins
1994	[76]	Mouse: Splenic lymphocytes from C3H/HeN mice treated with poly I:C and IFN-α, measured against YAC-1 targets, in vitro hyperthermia	41°–43°C	Thermotolerance
			40°C, 1 hr	Poly I: C or IFN-α treated cells rendered resistant to hyperthermia at 42°C. Viral infection, fever and IFN-α can render NK cells resistant to stress
1997	[78]	Human: Ocular Melanoma, in vitro hyperthermia using a water bath	39°–45°C	No significant difference in NK cell susceptibility of heated versus unheated cells
			45°C, 30 min	Reduced HLA-I and β-microglobin levels, elevated Hsp70, but unchanged Hsp60 levels
1997	[79]	Human: Ewing's sarcoma, K562 leukemia and EBV transformed B cells from peripheral blood of healthy volunteers, in vitro hyperthermia	41.8°C followed by 37°C recovery	De novo increase in HSP72 levels after hyperthermia is related to increased sensitivity of lysis by NK cells
1997	[66]	Mouse: B16 melanomas of different sizes treated with ethanol injection, IL-2 and local microwave hyperthermia	43°C, 15 min	Increased infiltration of NK cells
1997	[47]	Human: hyperthermic isolated limb perfusion (HILP) of melanoma patients, local hyperthermia	40.5–41.8°C, 60 min	NK cell activity increased with HILP
1998	[58]	Mouse: SCID mice with human breast xenografts, whole body hyperthermia	39.8°C, 6–8 hr	Increased NK cell infiltration, depletion of NK cells inhibits tumor cell apoptosis
1998	[126]	Human: healthy volunteers with catecholamine, growth hormone and β endorphin blockade, immersion in water bath up to the neck	39.5°C, 2 hr	Hyperthermia induced recruitment of NK cells to peripheral blood, unaffected with hormone blockade. NK activity (both naïve and IFN-α/IL-2 stimulated) did not change
1998	[82]	Human: renal cell carcinoma ACHN in vitro hyperthermia	41.8°C, 3 hr	Hyperthermia enhanced NK cytotoxicity of ACHN cells, blocked with anti-Hsp72 antibodies
1999	[64]	Rat: hyperthermia with immersion into waterbath, induced peritonitis 8 hours after hyperthermia	42°C, 15 min	Hyperthermia protective in sepsis reducing severity of peritonitis. Possible enhancement of immune effectors including NK cells
2000	[127]	Human: effect of in vitro hyperthermia on activity and generation of IL-2 activated NK cells	42°C, 1 hr	Hyperthermia transiently reduced lytic activity of NK cells. Heating target cells alone did not substantially modify their susceptibility to lysis induced by either NK or IL-2 activated NK cells
2000	[128]	Human and mouse: fibroblasts and NK cells, in vitro hyperthermia	39°C, 4-24 hr	Suppression of IFN mediated enhancement of NK cell activity in human and murine cells. Significant increase of both antiviral and antiproliferative activities of all three human interferons
2000	[50]	Human: healthy volunteers with whole body hyperthermia in 39°C water bath	38°C core temperatures	Increased NK cell count and activity
2000	[75]	Human: peripheral blood non- adherent cells, cytotoxicity measured against K562 and Raji cells, in vitro hyperthermia	42–42°C 1 hr, then cultured 7 days with IL-2	Cytotoxicity decreased at 42°C, but did not change at 40°C
2000	[129]	Mouse: IL-2 activated NK cells against T cell blasts, Cr51 assay, in vitro hyperthermia	40–41°C, 1–4 hr	Enhanced susceptibility to killing by syngenic IL-2 activated NK cells
2001	[130]	Rat: jaundice model, translocation of bacteria from gut and immune response, in vivo hyperthermia with water bath immersion	42°C, 15 min	NK cell number is elevated in hyperthermia group with respect to control
2001	[80]	Rat: T9 glioma cells, in vitro hyperthermia in a water bath	43°C 1 hr	Elevated MHC I and HSP70 levels (stable MHC II and ICAM levels). Splenic lymphocytes of rats injected with heated T9 cells displayed enhanced specific cytotoxicity
2002	[51]	Human: patients with advanced solid tumors, whole body hyperthermia	39°–39.5°C, 3–6 hr 39.5°–40°C, 6 hr	Transient decrease in number of circulating lymphocytes
2002	[81]	Human: osteo and chondrosarcoma cell targets, NK cells from peripheral blood of healthy donors, in vitro hyperthermia	42.5°C, 90 min	Lysis by NK cells was increased by heat treatment of the target cells. Hyperthermia increases HSP72 expression in sarcoma cells and their susceptibility to NK cell mediated lysis
2002	[65]	Rat: peritonitis model, in vivo hyperthermia	40°C and 42°C, 4 hr	NK cell amounts are found to be increased in the control peritonitis group. Hyperthermic preconditioning prior to peritonitis induction returned parameters to control levels
2002	[131]	Human: patients with various malignant diseases, whole body hyperthermia	41.8°C, 1 hr	Immediately after hyperthermia, drastic increase in peripheral NK cells, lost within 5 hr. CD56^+ cells reach maximum number 48 hr after hyperthermia
2003	[132]	Human: colorectal, germ line and ovarian cancer patients, multiple hyperthermia treatments, whole body hyperthermia	41.8°C, 1 hr	Significant elevation of NK cell numbers during hyperthermia. Levels dropped significantly 20 hr after with apoptosis
2005	[90]	Mouse: B16 melanoma in combination therapy with hyperthermia and DC, hyperthermia with magnetic cationic liposomes	43°C, 30 min	Increased NK cell activity of splenocytes from combination-therapy cured mice
2005	[52]	Human: patients with advanced malignancies, whole body hyperthermia	41.8°–42.2°C	NK cell numbers increased, plasma IL-12 levels and IFN-γ/IL-10 ratio were decreased transiently
2005	[86]	Mouse: Tumors in C57BL/6 mice, whole body hyperthermia	40°C, 2 hr daily	No change in splenic NK cell population
2005	[133]	Human: patients with hepatocellular carcinoma, local hyperthermia with RF heating device powered to 614-1363W- no thermometry	1 hr, 1–2 times a week	Early (20 min) enhanced activation of NK cells
2005	[134]	Mice: C57BL/6 and rag2 −/− mice whole body hyperthermia	42°C 1 hr	Hyperthermia decreased perforin and granzyme message in spleen
2006	[53]	Human: cancer patients with solid tumors and healthy volunteers, whole body hyperthermia	41°–41.8°C, 1 hr	Increased NK cells shortly after WBH
2006	[56]	Human: melanoma, colon carcinoma, non-small cell lung cancer and cervical carcinoma cell lines used as targets for IL-2 activated NK cells from healthy donors, in vitro hyperthermia in a water bath	42°C 1 hr	Increased NK cell cytotoxicity in vitro against heat shocked cell lines
2007	[59]	Mouse: B16F10 melanoma, in vivo local microwave or in vitro hyperthermia using an incubator	42°C, 7–10 min, 1–3 times	Splenocytes from hyperthermia treated mice show increased cytotoxicity against YAC-1 tumor cells. In vitro heating of NK and/or tumor targets enhances specific cytotoxicity
2007	[57]	Human: peripheral blood from healthy volunteers, in vitro hyperthermia	39.5°–42°C, 6 hr	Thermal stress enhanced NK cytotoxicity against Colo205 cells. In vitro heating of NK and/or tumor targets enhanced specific cytotoxicity
2007	[54]	Human: peripheral blood from healthy volunteers, whole body hyperthermia with water bath immersion	39.4°C, 30 min	Increased numbers of NK cells circulating in peripheral blood

Figure 1. Summary of preclinical and clinical studies that have investigated NK cell responses to hyperthermia. NK cells can be activated through a series of activating and inhibitory receptors, and the balance of these signals decides the fate of NK cell cytotoxic activity. The reported effects of hyperthermia on NK cell cytotoxicity, distribution in the periphery and cell number and infiltration into tumor beds are summarized in this schematic.

Figure 2. Hypothetical model for effects of hyperthermia enhanced cytotoxicity. (1) Hyperthermia acts on both NK cells and tumor targets independently. (2) Thermal enhancement of the membrane clustering of the NKG2D stimulatory receptors on the NK cell surface membrane has been reported on NK cells. (3) Increased expression of stimulatory ligands on tumor cells (e.g. MICA, Hsp70) has been found with hyperthermia, and this increase might be accompanied by (4) a decrease of MHC class I expression on tumor cell surface, which could further activate NK cells. (5) Tumor derived Hsp70 has also been suggested to be presented to NK cells indirectly by antigen presenting cells. (6) These changes result in enhanced killing of tumor targets by NK cells.

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