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Harnessing the epigenome to boost immunotherapy response in non-small cell lung cancer patients.

ABSTRACT: The introduction of immune checkpoint inhibitor (ICI)-based therapy for non-oncogene addicted non-small cell lung cancer (NSCLC) has significantly transformed the treatment landscape of the disease. Inhibitors of the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint axis, which were initially considered as a late-line treatment option, gradually became the standard of care as first-line treatment for subgroups of NSCLC patients. However, a significant fraction of patients either fails to respond or progresses after a partial response to ICI treatment. Thus, the identification of mechanisms responsible for innate and acquired resistance to immunotherapy within a rapidly evolving tumor microenvironment (TME) is urgently required, as is the identification of reliable predictive biomarkers beyond PD-L1 expression. The deregulation of the epigenome is a key driver of cancer initiation and progression, and it has also been shown to drive therapeutic resistance. Tumor education of infiltrating myeloid cells towards an immuno-suppressive phenotype as well as induction of T-cell dysfunction in the TME is also driven by epigenome reprogramming. As it stands and, given their dynamic nature, epigenetic changes in cancer and non-cancer cells represent an attractive target to increase immunotherapy activity in NSCLC. Accordingly, clinical trials of combinatorial immuno-epigenetic drug regimens have been associated with tumor response in previously immunotherapy-resistant NSCLC patients irrespective of their PD-L1 status. Moreover, epigenetic signatures might represent valuable theragnostic biomarkers as they can be assayed easily in liquid biopsy and provide multiple layers of information. In this review, we discuss the current knowledge regarding the dysregulated epigenetic mechanisms contributing to immunotherapy resistance in NSCLC. Although the clinical data are still maturing, we highlight the attractive perspective that the synergistic model of immuno-epigenetic strategies might overcome the current limitations of immunotherapy alone and will be translated into durable clinical benefit for a broader NSCLC population.

SUBMITTER: Gkountakos A

PROVIDER: S-EPMC8161860 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionThe spleen is a lymphoid organ and we hypothesize that clinical benefit to immunotherapy may present with an increase in splenic volume during treatment. The purpose of this study was to investigate whether changes in splenic volume could be observed in those showing clinical benefit versus those not showing clinical benefit to pembrolizumab treatment in non-small cell lung cancer (NSCLC) patients.Materials and methodsIn this study, 70 patients with locally advanced or metastatic NSCLC treated with pembrolizumab; and who underwent baseline CT scan within 2 weeks before treatment and follow-up CT within 3 months after commencing immunotherapy were retrospectively evaluated. The splenic volume on each CT was segmented manually by outlining the splenic contour on every image and the total volume summated. We compared the splenic volume in those achieving a clinical benefit and those not achieving clinical benefit, using non-parametric Wilcoxon signed-rank test. Clinical benefit was defined as stable disease or partial response lasting for greater than 24 weeks. A p-value of <0.05 was considered statistically significant.ResultsThere were 23 responders and 47 non-responders based on iRECIST criteria and 35 patients with clinical benefit and 35 without clinical benefit. There was no significant difference in the median pre-treatment volume (175 vs 187 cm3, p = 0.34), post-treatment volume (168 vs 167 cm3, p = 0.39) or change in splenic volume (-0.002 vs 0.0002 cm3, p = 0.97) between the two groups. No significant differences were also found between the splenic volume of patients with partial response, stable disease or progressive disease (p>0.017). Moreover, there was no statistically significant difference between progression-free survival and time to disease progression when the splenic volume was categorized as smaller or larger than the median pre-treatment or post-treatment volume (p>0.05).ConclusionNo significant differences were observed in the splenic volume of those showing clinical benefit versus those without clinical benefit to pembrolizumab treatment in NSCLC patients. CT splenic volume cannot be used as a potentially simple biomarker of response to immunotherapy.

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Harnessing the epigenome to boost immunotherapy response in non-small cell lung cancer patients.

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