While, of neoantigen generation before or at the time

While,
unconventional in light of the extensive efforts that have been directed
towards the development of drugs capable of restoring the function of tumor
suppressing proteins (in the hope that they might then exert antitumor effects),
the data of the article indicates that permanent inactivation (instead of
reactivation) of particular tumor suppressors involved in DNA repair could be
used for therapeutic purposes. The reasoning is that the vigorous increase of
mutations in cancer cells could possibly result in immune responses.

Inactivation of mismatch repair leads to an increase of indels and these indels
result in frameshifts that generate neoepitopes. Accordingly, a DNA repair
deficiency that leads to indel-resultant frameshifts might be behind the significant
changes in immune surveillance that were observed at inactivation of MLH1 in
mouse cancer cells. Results obtained with TMZ suggest that drugs that inactivate
DNA repair in cancer cells could be systemically acceptable. However, this does
not mean that increasing tumor heterogeneity with chemotherapy is an effective way
to encourage immune surveillance. But it can be interpreted from these results
that it is possible to inactivate DNA repair “in vivo” to advance immune
surveillance and responses to immune-checkpoint blockade. The data of the
article supports the exploitation of neoantigen generation before or at the
time of a profound bottleneck. This is based on results showing that, when limited
to a clonal population, the dynamic generation of neoantigens propelled by MMR
deficiency further develops immune detection and accordingly, tumor debulking
and initiation of MMR deficiency may be coupled to obtain effective results. Genes
such as MLH1, involved in DNA repair, could be targeted to increase mutational
load. Mismatch repair proteins and DNA polymerases have well-characterized enzymatic
activity, which is agreeable to pharmacological blockade. This study reasoned
that ectopically increasing the mutational burden in cancer cells may, ironically,
be advantageous for therapeutic purposes. Therefore, how to increase mutational
load in cancer cells using pharmacological agents was considered. The data of
this article advocate that the inactivation of DNA mismatch repair causes a
hyper-mutation status that increases tumor neoantigens, and then triggers
long-lasting immune surveillance that can be further enhanced by immune modulators.

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