I've mentioned, in the past, that there were insufficient efforts to find T cells in humans that would/could recognize common cancer-related mutations..... mostly in context of tyrosine kinases.
The gene that codes for p53 (TP53) is the most commonly mutated gene among human cancers, but it has proven difficult to make "drugs" that recognize those mutations. p53 itself is a "tumor suppressor" that binds to target DNA sequences and thus activates genes that repair damaged DNA. Certain mutations in TP53 thus allow the accumulation of cells with damaged DNA.
Switching topic....... "neoantigens" are changes to (largely) proteins that are SPECIFIC to cancers.... they are sequences of amino acids that are not found on/in normal human cells. Most cancer antigens that are studied in clinical trials have been (and still are, unfortunately) tumor ASSOCIATED antigens, not tumor specific antigens..... think NY-ESO-1, which is expressed on normal cells from the testes.
These authors find cancer-unique p53 sequences that are recognized by patient T cells, isolated from INSIDE their own cancers.
But T cells don't willy-nilly recognize and respond to anything foreign (in this case, protein sequences dictated by the TP53 mutations). Foreign antigens need to be "presented" to T cells by components of the major histocompatibility complex, the class I and class II HLA antigens in humans. The presentation occurs on the surface of antigen presenting cells, most famous among which are dendritic cells. Only certain of these HLA determinants (extremely heterogeneous, human to human) will pair with a given antigen (in this case, mutant p53), and thus the response to any antigen is "restricted" by a patient's HLA profile. One may have perfectly good mutations for the induction of cancer-protective immunity, but it's moot if your HLA profile doesn't match up with the mutation for presentation.
So, to mount an effective response to a given cancer, your cancer needs to have a neoantigen or neoantigens which pairs/pair with one of your presenting class I or class II HLA molecules. Otherwise, "restriction" dictates bad news.
This is a simplified explanation. Exceptions abound.
Trust me, most highly trained biologists can't read this manuscript and make sense of it. Lucky, I started out studying neoantigens in chemically-induced sarcomas, and fell into the thick of things with MHC restriction, thereafter specializing in class I- and class II-specific MAbs. Didn't have the emotional stability to make it a career, but it's certainly been a great ride, sight seeing. |
