Tumor cell apoptosis, lymphocyte recruitment and tumor vascular changes are induced by low temperature, long duration (fever-like) whole body hyperthermia

Abstract

A single treatment of low-temperature, long-duration, whole-body hyperthermia of either severe combined immunodeficient (SCID) mice bearing human breast tumor xenografts or Balb/c mice bearing syngeneic tumors for 6-8 hr can cause a temporary reduction of tumor volume and/or a growth delay. In both animal model systems, this inhibition is correlated with the appearance of large numbers of apoptotic tumor cells. Because this type of mild heat exposure, comparable to a common fever, is not itself directly cytotoxic, other explanations for the observed tumor cell death were considered. Our data support the hypothesis that this hyperthermia protocol stimulates some component(s) of the immune response, which results in increased antitumor activity. In support of this hypothesis, increased numbers of lymphocyte-like cells, macrophages, and granulocytes are observed in the tumor vasculature and in the tumor stroma immediately following this mild hyperthermia exposure. In Balb/c mice, an infiltrate persists in the tumor for at least 2 weeks. Using the SCID mouse/human tumor system, we found that both host natural killer (NK) cells and injected human NK cells were increased at the site of tumor following hyperthermia treatment. Experiments using anti-asialo-GM1 antibodies indicate that the tumor cell apoptosis seen in the SCID mouse appears to be due largely to the activity of NK cells, although additional roles for other immunoeffector cells and cytokines appear likely in the immunologically complete Balb/c model. Another interrelated hypothesis is that immunoeffector cells may have greater access to the interior of the tumor because we have observed that this treatment causes an obvious expansion in the diameter of blood vessels within the tumor and an increase in nucleated blood cells within the vessels, which persists as long as 2 weeks after treatment. Further study of the mechanisms by which mild hyperthermia exerts antitumor activity could result in this treatment protocol being used as an effective, nontoxic adjuvant to immunotherapy and/or other cancer therapies.

Short-Term Hyperthermia Promotes the Sensitivity of MCF-7 Human Breast Cancer Cells to Paclitaxel

“…16,21) In fact, caspase-3 and caspase-7 share similar substrate specificity, 22) and the induction of apoptosis by anti-cancer agents through the activation of caspase-7 independent of caspase-3 has been documented. 23) The limitation of conventional approach for hyperthermia is the uneven thermal effect, 10,15) for thermal energy was conducted from a heat source, and therefore the healing effect maybe different depended on the distance from the heat source. one of the advantages of microwave heating used in the present study is a precise manipulation of temperature.…”

“…10) In addition to a direct effect, the enhancement of the cytotoxicity of chemotherapeutic agents at around 41°C has also been well characterized. 11,12) The purpose of the present study was to determine the effects of short-term hyperthermia at 41°C for 2 h on PTX-induced anti-tumor activity using human breast cancer MCF-7 cells.…”

Characterization of Heat Shock Protein 110 and Glucose-Regulated Protein 170 as Cancer Vaccines and the Effect of Fever-Range Hyperthermia on Vaccine Activity

“…At the cellular level, it has been shown that fever-like treatments of lymphocytes (39.5°C for 6 -8 h) leads to activation of protein kinase C, massive cytoskeleton changes characteristic of a heightened activation status, and the induction of hsps including hsc70 and hsp110 (22, 48 -49). In mice, fever-level hyperthermia has been shown to lead to an antitumor effect involving both the innate and specific immune systems (50). It is possible that mild hyperthermia, which is nontoxic, may lead to several changes in immunological parameters.…”

Primary immune surveillance: some like it hot

“…It remains to be determined if hyperthermia can exploit IL-6 and the soluble IL-6 receptor in the tumor microenvironment to improve vascular adhesion similar to that observed in HEVs. In addition to changes in tumor blood flow and oxygenation associated with hyperthermia [44], improved vascular adhesion may theoretically enhance T lymphocyte infiltration into tumor sites, as has been reported for natural killer lymphocytes [22]. T lymphocyte infiltration is critical to antitumor responses and improved patient survival [45][46][47].…”

“…As a nontoxic treatment, whole-body hyperthermia (WBH) maintains an elevation of core body temperature by isolating an organism in a contained, temperaturecontrolled environment, thereby mimicking the thermal component of fever [12,21,22]. As previously stated, elevated core body temperatures in the febrile range have been associated with improved survival in homeotherms and poikilotherms; however, alterations in the immune system during thermal stress were largely undefined.…”