ESTRO 2024 - Abstract Book

S5219

Radiobiology - Microenvironment

ESTRO 2024

Results:

Mass spectrometry-based metabolomics revealed that NSCLC cell models excessively consume ser/gly synthesis pathway metabolites as response to RT treatment. This observation was validated in blood plasma samples from patients with NSCLC presenting a reduction in ser/gly pathway metabolites after their first and last RT cycle. In addition, NSCLC cell models showed elevated expression of the serine to glycine conversion enzyme SHMT2 in response to RT. Using SHMT inhibitor sertraline in combination with RT hindered the growth of NSCLC cells and reduced their clonogenic and intrinsic NSCLC stem cell self-renewal capacity. This phenotype was accompanied by an increase in reactive oxygen species (ROS). In immunocompetent mice bearing subcutaneous lung tumors, we confirmed a significant reduction in tumor growth solely in the group receiving sertraline and RT combination treatment. Notably, tumor weights were linked to ser/gly pathway metabolite levels in the blood serum. Sertraline blocked the serine to glycine conversion in vivo , which became most apparent when the tumor’s requirement for ser/gly pathway metabolites was enhanced upon RT exposure, highlighted by an increase in SHMT2 expression. As a result, ser/gly pathway metabolites were altered both locally and systemically, observing decreased glycine and downstream threonine levels in the blood serum. These metabolic changes were linked to remodeling of the tumor microenvironment by cytokine release to support natural killer (NK)-related immune signatures. The combination treatment led to a reduction of CCL2 cytokine levels, associated to immune suppression and poor prognosis, and increased levels of cytokines that enhance anti-tumor responses, such as CCL6 (7, 8). The NK-related changes were confirmed by eradication of the immune checkpoint protein galectin-1, accompanied by elevated levels of granzyme B. Therefore, the improved anti-tumor responses resulted from restricting the metabolite availability required for the recovery of tumor cells from RT, while simultaneously promoting immune attraction and infiltration.

Conclusion:

Our findings underscore that targeting ser/gly metabolism using sertraline limits cancer cell specific recovery from RT and provides tumor control through immunomodulation in NSCLC. In addition, this study serves as a starting point for future investigations targeting ser/gly metabolism in combination with RT to improve immunotherapy responses in NSCLC.