Hyperthermia and the Immune System

Hyperthermia (HT) makes the immune system become actively engaged against tumours. Yes, HT actually induces anti-tumour immunity, creating a type of “personalized” treatment approach. One of the most eloquent papers summarizing the known immune responses to HT was just accepted for publication March 2012 (Frey B, Weiss EM, et al. Old and new facts about hyperthermia-induced modulations of the immune system. Int. J. Hyperthermia, 2012, 1–15, Early Online).

When discussing HT, we are discussing a treatment that can kill cancer cells through several mechanisms, makes chemotherapy and radiotherapy work better, and stimulates an immune attack against the targeted lesion(s). In this post, I will endeavor to provide an overview of the immune responses described in Frey’s paper.

First some basics…

• Since the time of Dr. William Coley, researchers have been trying to find the optimal “vaccine” with which to treat cancers. If only we could think of a way to get the immune system to attack the tumour itself. The search for the ideal bug or autologous (made from self) vaccine is now at a frenzied pace, for good reason.
• Treatments such as dendritic cell vaccines, tumour-specific vaccines, and the various viruses and bacteria injected into patients; have been in use for decades. Since this idea of recruiting one’s own immune system to attack the tumour makes all the sense in the world.
• Immune stimulation by the use of HT treatment for malignancies requires minimum temperatures of 40 to 41 ℃, and for adequate amounts of time (known as the Arrhenius Relationship). Please note that all reference to HT treatment of cancer hereafter assumes optimized temperatures and times.
• For the understanding of this post, it is critical to know that there can be two types of immune response:
  • Innate – immune response that is non-specific, generalized and immediate.
  • Adaptive – immune response that is specific and targeted with cells that have been “educated” for a specific target.

Enter HT…

• Heated tumour cells develop damaged and unfolded proteins on their surfaces which make these cells recognizable by the innate immune system
• These damaged proteins on the cell surfaces of tumour cells look very different than healthy cells, which alarms the immune system
• Innate cells (such as Natural killer cells (NK) and granulocytes) are immediately sent to the tumour, recognizing these damaged and unfolded proteins
• These NK cells and macrophages then activate dendritic cells (DC)
• DC’s present the heat damaged proteins “collected” by the NK cells and macrophages to T cells (from the Adaptive Immune System)
• HT also promotes the maturing and migration of these DCs to the lymph nodes
• In the lymph nodes the T cells become “activated” or “educated” against these unfolded proteins on heated cancer cells (in a MHC-dependent manner for my fellow molecular biology buffs)
• The activated T cells are called Cytotoxic T Lymphocytes which attack and kill tumour cells
• This immune response is probably the main reason for the “bystander effect” or “Abscopal effect” of HT; Improvements to tumours in distant areas from the treatment site, noted in many HT studies

These HT-induced immune responses against the tumour has this paper calling HT “in situ tumour vaccination.” The point is that heat makes cancer cells look distinct from healthy cells, and attract an immune response that is both immediate and long-lasting. This is exciting and incredibly interesting to me. I hope this leads to further interest in this fascinating topic for the reader as well.

In Health,

Gurdev Parmar, B.Sc., ND

Definitions:

Lymphocytes

The chief cells of the Immune system, the real soldiers of the inherent army of our body are known as lymphocytes. Lymphocytes are small white blood cells and exist in two main forms: B cells and T cells (also known as B lymphocytes and T lymphocytes). The B cells produce antibodies that attack foreign molecules (germs and the toxins they produce). The T cells are defined below.

T cells

The abbreviation “T” stands for thymus, the organ in which their final stage of development occurs. Every effective immune response involves T cell activation; however, T cells are especially important in cell-mediated immunity, which is the defense against tumor cells and pathogenic organisms inside body cells. T cells contribute to your immune defenses in two major ways. Some help regulate the complex workings of the overall immune response, while others are cytotoxic and directly contact infected cells and destroy them. Chief among the regulatory T cells are helper T cells. They are needed to activate many immune cells, including B cells and other T cells. Cytotoxic T cells (sometimes called killer T cells) help rid your body of cells that have been infected by viruses as well as cells that have been transformed by cancer but have not yet adapted to evade the immune detection system.

Natural Killer cells

Natural killer cells (also known as NK cells, K cells, and killer cells) are a type of lymphocyte and a component of the innate immune system. This means that natural killer cells don’t have to recognize a specific abnormality on a cell to be able to do their job. NK cells play a major role in the host-rejection of both tumours and virally infected cells. NK cells combine with cancer cells or cells infected with viruses and release toxic granules into the abnormal cells, inducing apoptosis (natural cell death). In this role they are cytotoxic — that is, “cell killing.” NK cells also produce substances known as cytokines, which assist the body in removing viruses and tumor cells.

Macrophages

Macrophages (Greek: “big eaters”, makros = large, phagein = eat) are cells within the tissues that originate from specific white blood cells called monocytes. Monocytes and macrophages are phagocytes, acting in both nonspecific defense (or innate immunity) as well as specific defense (or cell-mediated immunity) of vertebrate animals. Their role is to phagocytize (engulf and then digest) cellular debris and pathogens either as stationary or mobile cells, and to stimulate lymphocytes and other immune cells to respond to the pathogen.

Dendritic cells

Dendritic cells are known as the most efficient antigen-presenting cell type with the ability to interact with T cells and initiate an immune response.

Abscopal effect

The Abscopal Effect is a phenomenon whereby localized treatment of a particular tumor site causes a response in an organ/site distant to the treated area.