57. Antitumor immunity. Evolution of immunity.

Antitumor Immunity

Basic Principle of Tumor Recognition

• The immune system’s fundamental role is to distinguish between what belongs to the body (self) and what does not (non-self).
• Cancer cells challenge this mechanism because they originate from self-cells but acquire changes that may make them appear partially foreign.
• Without the diversity of MHC molecules and the actions of cell-mediated immunity, cancers might have been contagious diseases. Tumors could have been grafted from one body to another much like infectious agents.
• This understanding originated from experiments in mice, where tumors transplanted between genetically distinct strains were rejected. In contrast, tumors transplanted within the same inbred strain were accepted and eventually killed the host.
• A striking real-world example is the Tasmanian devil, a species with little MHC diversity. When they bite one another, they can transmit facial tumors due to the immune system’s inability to distinguish the tumor as foreign.

Tumor Antigens and Their Types

• Tumor antigens are classified as tumor-specific antigens (TSAs) and tumor-associated antigens (TAAs).
• Tumor-specific antigens are present only on cancer cells and not found in normal tissues. These can arise due to genetic mutations creating new antigens (neoantigens), due to viral oncogenes introduced during infection, or due to integrated retroviruses.
• Tumor-associated antigens are normal proteins expressed inappropriately or in excess by tumor cells. These include proteins that are overexpressed, proteins from different tissue types, or those typically produced during fetal development but reactivated in cancer.
• Alpha-fetoprotein (AFP) is a classic example of a tumor-associated antigen. It is usually produced during fetal life and declines after birth. Elevated AFP in adults can signal certain cancers such as hepatocellular carcinoma.
• Not all antigens are proteins. Tumors also express abnormal sugars and lipid molecules on their surface due to errors in glycosylation pathways. These molecules resemble those found during fetal development and are common across many tumor types.
• The widespread presence of these molecules has led to the idea of developing a universal cancer vaccine. However, these molecules are not presented by MHC, making it hard to elicit a strong T cell response.

How the Immune System Fights Tumors

• Natural Killer (NK) cells play a key role in early tumor detection. They scan for cells with reduced or absent MHC class I molecules, a common feature in many tumor and virus-infected cells.