MHC Loss in Cancer: How Tumors Evade Immune Attack

The immune system identifies and eliminates threats like cancer, a disease of uncontrolled cell growth. Central to this defense is the Major Histocompatibility Complex (MHC), a group of proteins on the surface of most cells that act as a cellular identification system. MHC molecules distinguish the body’s healthy cells from abnormal ones. This article explores MHC’s function, its role in fighting cancer, how tumors evade it, and the implications for modern treatments.

MHC: The Immune System’s Cellular ID Scanner

The Major Histocompatibility Complex is a set of genes that code for proteins that function like a cellular display case. These MHC molecules present small protein fragments, called peptides, from within the cell on its surface. This allows immune cells, particularly T-cells, to monitor the health of cells by “scanning” these presented peptides to determine if a cell is healthy and belongs to the body.

This identification system has two primary classes. MHC Class I molecules are present on almost all nucleated cells and display peptides from proteins made inside the cell, offering a snapshot of its internal activities. This is how the immune system detects internal problems like viral infections or cancerous transformations.

MHC Class II molecules are found only on specific immune cells called antigen-presenting cells. These cells consume external material, break it down, and display fragments on their MHC Class II molecules. This process allows them to show other immune cells what they have found to coordinate a broader defensive response.

Flagging Cancer Cells for Immune Attack

Cancer development is driven by genetic mutations that produce abnormal proteins, known as tumor-associated antigens. The body’s immune system is designed to detect these changes and eliminate the cells before they form a tumor, a process that relies on MHC Class I molecules.

When a cell becomes cancerous, these abnormal proteins are broken down into peptide fragments. The MHC Class I molecules bind to these tumor-specific fragments and display them on the cell’s surface, acting as a red flag for the immune system.

Patrolling cytotoxic T-cells are trained to recognize these abnormal peptides. When a T-cell identifies a cancer-specific antigen displayed by an MHC Class I molecule, it initiates a direct attack, releasing toxic substances that kill the cancerous cell. The success of this response depends on the cancer cell’s expression of MHC Class I molecules.

How Cancer Becomes Invisible Through MHC Loss

Cancer cells are under immense pressure from the immune system, driving them to evolve survival strategies. A primary method of evasion is disrupting the MHC Class I antigen presentation pathway, a process known as MHC loss or downregulation. This allows cancer cells to become invisible to the immune cells hunting them.

Under constant threat from T-cells, cancer cells with lower levels of MHC Class I molecules are more likely to survive. This creates a selection pressure where the tumor population becomes dominated by cells that cannot present tumor antigens. This loss can happen through mutations in MHC genes or interference with the machinery that transports the molecules to the surface.

This loss of MHC expression is like a fugitive discarding their identification. Without the MHC molecules to present tumor antigens, cytotoxic T-cells cannot recognize the cancer cell as a threat. This immune evasion allows the tumor to grow unchecked, and the absence of MHC Class I molecules is a common finding in many advanced cancers.

Cancer Immunotherapy and the MHC Challenge

Immunotherapies are designed to boost a patient’s immune system to fight cancer. A class of these drugs, known as immune checkpoint inhibitors, works by “releasing the brakes” on T-cells, empowering them to attack cancer cells more aggressively. The effectiveness of these T-cell-based therapies, however, depends on the T-cell’s ability to recognize the cancer cell.

This recognition requires the cancer cell to present tumor antigens on its MHC Class I molecules. If a tumor has eliminated MHC expression, the therapeutic strategy is compromised. Empowered T-cells still cannot “see” their target, rendering the treatment ineffective and leading to primary or acquired resistance. This is a reason why immunotherapies may not work for all patients or can stop working over time.

Addressing this challenge is a focus of current cancer research. Scientists are exploring strategies to force cancer cells to restore their MHC Class I expression. Another avenue involves therapies that use other immune cells, like Natural Killer (NK) cells, which can recognize and kill cells that have lost their MHC molecules.