Cancer Immunology Theory

The Immune System Can Act
Against Tumour Cells

The immune system is primarily divided into two branches, the innate and adaptive systems. Acting together, these branches discriminate between normal cells (self) and foreign agents (non-self), including internal dangers such as cancer (altered self).¹ Though they derive from normal cells, tumour cells are recognized by the immune system due to danger signals released from tumour cells that elicit a downstream immune response.¹

Innate Immunity — The First Line of Defense Against Cancer

The innate immune system uses pattern recognition receptors to rapidly detect signals from a variety of sources to provide protection from foreign agents.¹ Outside of microbial infection, the innate immune system can also detect DNA replication errors, oxidative damage, and inflammation that is associated with tumour cells.¹ The system can then trigger downstream effector mechanisms to contain these tumour cells.¹

The major cellular players of this system are macrophages/granulocytes and Natural Killer (NK) cells.¹ These innate immune cells not only act within their own system, but also allow for the initiation and recruitment of the adaptive immune response.²

Adaptive Immunity — Immunologic Memory

The adaptive immune system responds to antigens to produce specific and long-lasting protection from foreign agents.¹ Once initiated, this system serves as an immunologic memory, remembering foreign antigens to produce a more immediate and vigorous response upon subsequent exposures.¹ Like the innate immune system, this adaptive response extends not only to pathogens but also cells recognized as altered self, which can include tumour cells.¹

The adaptive immune response is initiated by Antigen-Presenting Cells (APCs)—primarily dendritic cells—which internalize foreign proteins and present the processed antigens on their cell surfaces.¹ These cells can then stimulate antigen-specific T cells (cell-mediated immunity, involving the killing of target cells) and B cells (humoral immunity, involving the production of antibodies).¹

The Cancer–Immunity Cycle Theory

Adapted from Chen and Mellmann, 2013.³

The theorized cancer-immunity cycle is a multi-step process by which cancer immunity normally develops.² It suggests that APCs process and present cancer cell antigens to T-cells. Presentation of the antigen can then initiate a downstream effector T-cell response against the cancer-specific antigen, culminating in an immunologic response by effector T-cells against the cancerous cells.^2,3 Cancer cells may then release more cancer-specific antigens, starting the cycle over and thereby amplifying the response.^2,3

Cancer Immunoediting and Tumour Escape

If the Cancer-Immunity Cycle does not perform optimally, tumours can evade the immune system and continue to proliferate.³ The theorized process by which tumours can escape the immune system is termed cancer immunoediting, and consist of three phases: elimination, equilibrium, and escape (also known as the “three E’s of cancer immunoediting”).¹

Elimination
Refers to immune cells recognizing and eliminating cancer cells prior to becoming clinically apparent.

Equilibrium
Occurs when tumour growth is stopped, but not all tumour cells are eliminated. This phase is believed to be the longest, potentially extending for a person’s entire life, and culminating in one of two outcomes:
1. All tumour cells are eventually eliminated by the immune system.
2. Genetically unstable tumour cells, through prolonged interaction with the immune system, selects for immune-evasive mutations, leading to the escape phase.
Escape
Occurs when tumours are not recognized by the immune system and progress to become visible, coinciding with the manifestation of clinical symptoms. It has been demonstrated that tumours at this stage can avoid the immune system through direct and indirect mechanisms, which lead to their continued growth and metastases.

MANY CURRENT IO THERAPIES ARE THOUGHT TO TARGET TUMOUR ESCAPE MECHANISMS.¹

References: 1. Prendergast, GC et al. Cancer Immunotherapy: Immune Suppression and Tumor Growth. 2013. (Elsevier Science). 2. Butterfield, LH et al. Cancer Immunotherapy Principles and Practice. 2017. (Springer Publishing Company, Incorporated). 3. Chen, DS et al. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10.

The Immune System Can Act Against Tumour Cells

The Cancer–Immunity Cycle Theory

The Immune System Can Act
Against Tumour Cells