10 in a Million: making tumors visible to immune system

Another interesting study about tumor immunology from Nature Medicine. 

This time, the authors, led by Ton Schumacher at the Netherlands Cancer Institute, have examined cancer proteome (mutanome) from 5 melanoma patients using whole exome and RNA sequencing coupled with in vitro T cell assay to identify (1) an entire set of non-synonymous mutations within expressed genes and (2) immunogenic neo-antigens.

On average the authors found that melanoma patients expressed ~ 150 mutations per tumor. To identify immunogenic epitopes, 31-mer peptides corresponding to mutated portion of the proteins were synthesized, loaded into autologous, immortalized (via BCL6/BCL-XL transduction) B cells, serving as APCs, and cultured them with in vitro expanded tumor-derived CD4 T cells. With these methods, the authors were able to identify several tumor-specific, neo-antigens.

Importantly, sensitivity of tumor-associated CD4 T cells to mutant neo-antigens (open symbols) were on average 100-fold higher as compared to their wild-type variants (closed symbols), implying that mutant epitopes were quite immunogenic.

Interestingly, based on analyses of cancer mutation burden and clinical immune response, the authors speculated that mutation rates of at least 10 per megabase of coding genome provides sufficient load for formation of immunogenic neo-epitopes detected by immune system (for example, one patient, NKIRTIL045 had less than 10 mutations per megabase and did not show CD4 T cell response to mutated epitopes; see Fig. 1).  

In summary, all these recent studies and successes in cancer immunology clearly indicate that President Nixon's declaration of war on cancer has finally started to pay off.

David Usharauli