Neoepitopes of Cancers: Looking Back, Looking Ahead

Abstract

The search for specificity in cancers has been a holy grail in cancer immunology. Cancer geneticists have long known that cancers harbor transforming and other mutations. Immunologists have long known that inbred mice can be immunized against syngeneic cancers, indicating the existence of cancer-specific antigens. With the technological advances in high-throughput DNA sequencing and bioinformatics, the genetic and immunologic lines of inquiry are now converging to provide definitive evidence that human cancers are vastly different from normal tissues at the genetic level, and that some of these differences are recognized by the immune system. The very vastness of genetic changes in cancers now raises different question. Which of the many cancer-specific genetic (genomic) changes are actually recognized by the immune system, and why? New observations are now beginning to probe these vital issues with unprecedented resolution and are informing a new generation of studies in human cancer immunotherapy.

Fig. 1. Antigenic individuality of tumors

A given chemically induced tumor (as an example, A) elicits immunity against itself but not against other tumors (B, C, D, E or F), even though all tumors are induced by the same carcinogen, in genetically identical animals, and are histologically identical.

Fig. 2. A mechanism of generation of antigenic individuality in tumors

Random mutations (point mutations, translocations, insertions or deletions) occur in normal cells as a result of un-repaired errors in DNA replication (see panel A). The mutations will include one or more oncogenic (or driver) mutation (not shown), as well as many passenger mutations (colored circles within cells). These mutations occur at every division cycle and mark the lineage of that mutant cell as long as the mutation does not disadvantage the cell’s survival, or mutations in other cells do not give their bearers a survival advantage. Note how the tumor mass resulting from these divisions (and ongoing mutations) becomes highly heterogeneous with respect to mutations. The immunological consequences of these events were hypothesized in 1993 (Srivastava 1993) and are shown in panel B, which is adapted from a figure in that publication. Starting from two identical normal cells, which get transformed (Step 1) by the same driver oncogenic mutation (denoted in red as G), the progeny of each of the two transformed cells begin to differentiate from each other as a result of passenger mutations (denoted by random letters of the alphabet in black), which are random and hence unique to each tumor (Step 2). A subset of these mutations (mis-sense mutations) alters the sequences of expressed transcripts which are translated into mutated proteins and peptides derived from such mutated proteins. Some tumor cells may have more mutations than others (Vogelstein). Because of antigen processing (proteasomal activity, chaperoning of peptides by other molecules) and presentation, a subset of the mutated peptides are presented by the MHC I molecules of the tumor (Step 3). A subset of the MHC I-mutant peptide complexes will be recognized by the T cell receptors of T cells of the host. Peptide corresponding to an individual driver or passenger mutation may or may not be recognized by the immune system, but as a class, peptides encoded by passenger mutations are far more likely to be recognized by the immune system simply because passenger mutations are far more numerous. It is also conceivable teleologically that peptides derived from driver mutations are highly unlikely to be effective targets of immune response; should that be the case, the tumors would be eliminated very early during their progression. The heterogeneity of tumors with respect to passenger mutations also results in immunogenic heterogeneity of tumors.

Fig. 3. Pipeline for creation of a personalized set of cancer neoepitopes for each patient

Steps in red indicate those which are conceptually unclear, or difficult to accomplish in the high throughput manner required for clinical translation today. See text for detailed explanation.