A3.1 Immune checkpoint inhibitors

Topic

Checkpoint inhibitors act on the molecular brakes that the tumor itself uses to shut down the anti-tumor immune response: rather than directly attacking the tumor, these checkpoint inhibitors release a brake that the tumor had engaged on the patient's immune system.

The first of these molecular brakes works as follows: an inhibitory receptor on the T-cell surface binds to a complementary molecule expressed on the tumor cell's surface, and this binding sends an inhibitory signal to the T-cell. This inhibitory signal exhausts the T-cell, and as the T-cell becomes exhausted, its cytotoxic capacity—its ability to kill tumor cells—drops to zero.

The checkpoint inhibitor targeting this first molecular brake blocks precisely that interaction between the T-cell's inhibitory receptor and its complementary molecule on the tumor cell; by blocking this interaction, it prevents the inhibitory signal from being sent and restores the T-cell's cytotoxic capacity.

There is also a second molecular brake, distinct from the first, which acts earlier and in a different location: instead of acting within the tumor, this second molecular brake operates within the lymph nodes, where it limits the clonal expansion of tumor-specific T-cells—that is, it limits how many copies of these T-cells the immune system produces before they even get close to the tumor. The checkpoint inhibitor targeting this second molecular brake blocks this limitation, allowing a greater number of tumor-specific T-cells to multiply within the lymph nodes.

The underlying mechanism for both checkpoint inhibitors is the same pharmacological principle of receptor inhibition by a drug, applied here to the immunological synapse—the point of contact between the T-cell and the cell inhibiting it. The critical difference compared to other therapies that also inhibit receptors is that, in this case, the drug's molecular target is not located on the tumor cell itself, but rather on the patient's own T cell.

This is why the effect of checkpoint inhibitors does not occur immediately upon drug administration: first, the population of T cells with intact cytotoxic capacity must be restored or expanded; next, those T cells must physically enter the tumor; and only then can they carry out the cytotoxic function within the tumor—a function the tumor had previously suppressed. This sequence of steps explains the latency period of several weeks typically observed between drug administration and the tumor's response; it also encapsulates the purpose of checkpoint inhibitors: releasing the molecular brake the tumor had applied to the T cell, allowing the cell to resume the activity the immune system was already capable of performing before the tumor shut it down.

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