Why does T-cell Cancer Therapy require a large tumor mutanome?

Question

An article I read about Neuroblastoma states that the fact that Neuroblstoma has a small mutanome means that it is not viable to apply the classic T-cell immunotherapy. Why is this so? The article can be found here: Neuroblastoma: Developmental Biology, Cancer Genomics, and Immunotherapy

Answer 1

Understanding the link between the size of the tumor mutanome and its immunogenicity requires a basic understanding of T-cell development and regulation.

When normal human cells degrade proteins via the proteasome, some fragments of these proteins, called peptides, are bound to specialized cell-surface proteins called MHC. T-cells express a specialized receptor, called the TCR, which recognizes peptides bound by MHC proteins on other cells. The specificity of the TCR, what peptide/MHC combinations a T-cell can recognize, is randomly generated by targeted mutations and VDJ recombination in the TCR genes during a T-cells development. Each clonal population of T-cells (T-cells derived from the same precursor) have a unique TCR that recognizing different peptide/MHC pairs. When a T-cell's TCRs recognize a peptide/MHC combo on another cell, the T-cell is activated.

Because the TCR is generated randomly, many TCRs in T-cell precursors can recognize peptides derived from normal human proteins. To prevent these precursors from becoming T-cells that can attack the body, they are regulated in several ways. Many self-peptide recognizing precursors are destroyed in development, others are converted into regulatory T-cells that instead produce anti-inflammatory cytokines that tune down immune responses. Those those that escape these regulatory processes are later inactivated by other means.

What does this have to do with cancer? Well, most of a tumor's proteins are normal human proteins, and the human body does its best to suppress immune responses against normal human proteins, making it hard to generate an attack against cancer cells with T-cells that recognize normal self-peptide/MHC. Worse, overcoming this protective response could lead to an auto-immune attack on normal, healthy cells. Therefore, we want to make or use T-cells that recognize mutant-peptide/MHC combos. Such cells would not attack or be effectively suppressed in normal tissues, but could attack tumors.

However, to get these ideal, tumor-targeted T-cells, we need the tumor to produce mutant proteins whose peptide fragments ARE DISTINCT from the peptide fragments of normal proteins. Some tumors have far more of these kinds of mutations than others, and not every mutation is immunogenic (not every mutation can be differentially recognized by T-cells). For example, point mutations (single amino acid changes) that activate proto-oncogenes like BRAF don't necessarily lead to the production of structurally different peptide fragments. A larger mutanome offers a greater chance of immunogenic mutations.