Why Don't the Mutant Cells That Evade DNA Repair Cause Cancer More Frequently? Importance of the Innate Immune System in the Tumor Microenvironment

The standard of care for most malignant solid tumors still involves tumor resection followed by chemo- and radiation therapy, hoping to eliminate the residual tumor cells. This strategy has been successful in extending the life of many cancer patients. Still, for primary glioblastoma (GBM), it has not controlled recurrence or increased the life expectancies of patients. Amid such disappointment, attempts to design therapies using the cells in the tumor microenvironment (TME) have gained ground. Such immunotherapies have so far overwhelmingly used genetic modifications of Tc cells (Car-T cell therapy) or blocking of proteins (PD-1 or PD-L1) that inhibit Tc-cell-mediated cancer cell elimination. Despite such advances, GBM has remained a Kiss of Death for most patients. Although the use of innate immune cells, such as the microglia, macrophages, and natural killer (NK) cells, has been considered in designing therapies for cancers, such attempts have not reached the clinic yet. We have reported a series of preclinical studies highlighting strategies to re-educate GBM-associated microglia and macrophages (TAMs) so that they assume a tumoricidal status. Such cells then secrete chemokines to recruit activated, GBM-eliminating NK cells and cause the rescue of 50-60% GBM mice in a syngeneic model of GBM. This review discusses a more fundamental question that most biochemists harbor: since we are generating mutant cells in our body all the time, why don't we get cancer more often? The review visits publications addressing this question and discusses some published strategies for re-educating the TAMs to take on the sentry role they initially maintained in the absence of cancer.

Automated summary

The standard treatment for most malignant solid tumors involves tumor resection followed by chemo- and radiation therapy. However, this approach has not been effective in controlling recurrence or increasing the survival rate of primary glioblastoma (GBM) patients. Immunotherapies that use genetic modifications of Tc cells or inhibition of proteins have not been successful in treating GBM either. A series of preclinical studies have shown that re-educating GBM-associated microglia and macrophages (TAMs) can lead to the recruitment of activated, GBM-eliminating NK cells and rescue GBM mice. This review discusses the question of why we don't get cancer more often and strategies for re-educating TAMs to take on their original role as sentinels.