Natural killer cells limit the clearance of senescent lung adenocarcinoma cells.

Senescence is an important p53-controlled tumor suppressor program that not only opposes the proliferation of cancer cells but also promotes their immune-mediated clearance in certain contexts. In hepatocellular cancer, p53 induction promotes an innate immune cell-mediated clearance of senescent cells wherein natural killer (NK) cells seem to play the primary sentinel role. Whether NK cells also surveil cancer cells in other tumor types when p53 is activated to promote a senescence response is unknown. To identify the role that NK and other innate immune cell types have on the surveillance and destruction of lung adenocarcinoma cells, we developed an orthotopic transplantation model where p53 gene function could be restored to induce senescence after successful engraftment of tumor cells in the mouse lung. Contrary to precedent, we found that NK cells actually limited the efficient clearance of tumor cells from the mouse lung after p53 restoration. Instead, activation of p53 induced the infiltration of monocytes, neutrophils, and interstitial macrophages. Loss of NK cells further promoted expansion of these inflammatory cell types and tumor clearance after p53 restoration. These observations suggest that NK cell responses to p53 activation in lung adenocarcinoma is distinct from those found in other tumor types and that diverse innate immune cell populations may play context-dependent roles during tumor immune surveillance. Further, our data provide an impetus to understand the broader mechanisms that regulate cancer cell destruction by multiple cell types of the innate immune system and distinct cancer contexts.

Recombinase-based conditional and reversible gene regulation via XTR alleles.

Synthetic biological tools that enable precise regulation of gene function within in vivo systems have enormous potential to discern gene function in diverse physiological settings. Here we report the development and characterization of a synthetic gene switch that, when targeted in the mouse germline, enables conditional inactivation, reports gene expression and allows inducible restoration of the targeted gene. Gene inactivation and reporter expression is achieved through Cre-mediated stable inversion of an integrated gene-trap reporter, whereas inducible gene restoration is afforded by Flp-dependent deletion of the inverted gene trap. We validate our approach by targeting the p53 and Rb genes and establishing cell line and in vivo cancer model systems, to study the impact of p53 or Rb inactivation and restoration. We term this allele system XTR, to denote each of the allelic states and the associated expression patterns of the targeted gene: eXpressed (XTR), Trapped (TR) and Restored (R).