The mutational burden of non–small-cell lung
cancer (both squamous-cell carcinoma and adenocarcinoma)
may be the Achilles’ heel of immunotherapy.
The iatrogenic effect of mutagenic
therapy may need to be considered when determining
the order of therapeutic regimens, since some
cytotoxic chemotherapies and radiation may increase
the acquisition of new subclonal mutations
that might affect the response to immunotherapy.
Furthermore, current approaches to the
prediction of the development of tumor neoantigens
are relatively rudimentary and are restricted
to class I rather than class II major-histocompatibility-
complex (MHC) antigens. Efforts to better
delineate the development of both MHC class I–
and class II–restricted neoantigens may improve
our understanding of immune surveillance during
tumor evolution. Finally, understanding the
ways in which the immune microenvironment edits
the cancer genome during the disease course and
the ways in which the host immune system might
be leveraged to target tumor neoantigens within
the context of a heterogeneous genomic landscape
may provide promising avenues to improve
survival outcomes in patients with lung cancer.