  Immunotherapy has recently shown important clinical successes in a
substantial number of oncology indications. Additionally, the tumor somatic
mutation load has been shown to associate with response to these therapeutic
agents, and specific mutational signatures are hypothesized to improve this
association, including signatures related to pathogen insults. We sought to
study in silico the validity of these observations and how they relate to each
other. We first addressed whether somatic mutations typically involved in
cancer may increase, in a statistically meaningful manner, the similarity
between common pathogens and the human exome. Our study shows that common
mutagenic processes increase, in the upper range of biologically plausible
frequencies, the similarity between cancer exomes and pathogen DNA at a scale
of 12-16 nucleotide sequences and established that this increased similarity is
due to the specific mutation distribution of the considered mutagenic
processes. Next, we studied the impact of mutation rate and showed that
increasing mutation rate generally results in an increased similarity between
the cancer exome and pathogen DNA, at a scale of 4-5 amino acids. Finally, we
investigated whether the considered mutational processes result in amino-acid
changes with functional relevance that are more likely to be immunogenic. We
showed that functional tolerance to mutagenic processes across species
generally suggests more resilience to mutagenic processes that are due to
exposure to elements of nature than to mutagenic processes that are due to
exposure to cancer-causing artificial substances. These results support the
idea that recognition of pathogen sequences as well as differential functional
tolerance to mutagenic processes may play an important role in the immune
recognition process involved in tumor infiltration by lymphocytes.
