Hyperthermia and Immunity. A Brief Overview

After many years, hyperthermia (HT) is experiencing a new resurgence as seen by the positive results of many randomized trials all over the world. Tumour immunity similarly is suggested as the fourth modality of therapy for metastatic tumours from renal carcinoma and melanoma. An overwhelming amount of data from animal models and human patients indicate that whole body and locoregional hyperthermia exerts many biological and therapeutic effects on immune competent cells and cytokines. Among these effects, hyperthermia has recently been demonstrated to enhance the antigen presentation and consequently the activity of dendritic cells. This improvement is obtained through several mechanisms: a) increased lymphocyte recruitment and trafficking into the tumour area; b) increased immunogenicity of heat treated tumour cells; and c) increased production of the heat-shock proteins and costimulatory molecules. The effects and mechanisms of HT on immunity, lymphocyte recruitment and dendritic cell stimulation by heat shock proteins are reviewed here. Moreover the use of HT as an innate immunity booster in association with biological response modifiers is suggested. Tumour regression in vivo is mediated by a complex interplay between the innate immune system and adaptive immune response (1). The innate mechanism may trigger inflammatory events in the tumour microenvironment and in the presence of locally adequate cytokine combinations stimulate dendritic cells (DCs), the most specialized antigen presenting cells, to react against tumour specific surface antigens (TAA) (2). DCs are potent antigen presenting cells that exist in virtually every tissue, they capture antigens and migrate to secondary lymphoid organs where they activate naive T-cells. DCs in the presence of an adequate co-stimulation have the unique ability to activate the naive CD4+ and tumour specific cytotoxic lymphocytes CD8+ cells (CTLs) and sustain the primary immune response. DCs have been identified in different organs as essential components of the innate and adaptive immune systems. They have the ability to generate CTLs that recognize and kill virally infected or transformed cells. Tumour destruction by CTLs generally occurs in an antigen-specific, major histocompatibility complex (MHC)- restricted fashion. On the contrary CD3-natural killers (NKs) which are part of the innate immunity against tumours, are cells morphologically and functionally distinct from CD8+ and inhibit tumour growth in an MHC-non restricted manner. The killing activity of NK-cells is tightly regulated by a balance of signals integrated from inhibitory and activating receptors expressed on their surfaces (1, 3). NKG2D is one of these surface receptors and has been recognized as a primary cytotoxicity receptor and of pivotal importance for priming a Th1 antitumour T-cell response. NKG2D has been recognized also to be an ancestral defence system and part of the innate immunity reaction against tumours. Furthermore, NK-cells and dendritic cells interact with each other in the coordination of innate and adaptive immune responses as demonstrated by Walzer et al. (4). Epidemiological studies and sporadic observations have described spontaneous regression of cancer associated with the induction of fever, and of cellular immunity (5, 6). The crucial importance of fever in these regressions justifies the attempt to induce artificial thermal elevation of body temperature (whole body hyperthermia) for mimicking natural fever effects on cancer (7).