Predictive biomarkers of response to immunotherapy in triple-negative breast cancer - state of the art and future perspectives.

BACKGROUND: Immunotherapy by using immune checkpoint inhibitors (ICIs) heralded a new era in the treatment of patients with advanced triple-negative breast cancer (TNBC). Nevertheless, in a substantial proportion of TNBC patients, the clinical outcomes of ICIs treatment remain unpredict-able and proper bio-markers to identify tumors sensitive to immunotherapy are urgently needed. Currently, the most clinically relevant bio-markers used to predict efficacy of ICIs in patients with advanced TNBC remain the immunohistochemical analysis of programmed death-ligand 1 (PD-L1) expression, the assessment of tumor infiltrating lymphocytes (TILs) present in the tumor microenvironment (TME), and the evaluation of the tumor mutational burden (TMB). Emerging bio-markers related to activation of the transforming growth factor beta signaling pathway, the discoidin domain receptor 1, and thrombospondin-1 as well as other cellular and molecular factors present within TME, have the potential to be utilized as predictors of response to ICIs in the future. PURPOSE: In this review, we summarize the current knowledge of mechanisms regulating PD-L1 expression, of the predictive value of TILs as well as of associated cellular and molecular components present in the TME in TNBC. Furthermore, TMB and emerging bio-markers with potential value in predicting efficacy of ICIs are discussed, and new therapeutic strategies will be outlined.

Programmed death-ligand 1 expression in non-small cell lung carcinoma - mechanism of regulation, association with other markers, and therapeutic implication.

BACKGROUND: Immune checkpoint inhibitors (ICI) targeting the programmed cell death protein 1 (PD-1) signaling pathway have dramatically improved the clinical outcomes of oncological patients having advanced non-small cell lung carcinoma (NSCLC). The immunohistochemical analysis of programmed death-ligand 1 (PD-L1) expression remains the most widely used and clinically validated bio-marker predicting efficacy of ICI in NSCLC patients, but it represents in isolation an imperfect tool. The PD-1 axis is intricately coupled with numerous cellular and molecular factors within the tumor microenvironment (TME) of NSCLC. Cellular factors implicated in the regulation process of PD-L1 expression in NSCLC are related to the activity of tumor infiltrating lymphocytes and cancer associated fibroblasts. Intrinsic molecular factors which affect the level of PD-L1 expression are associated with the presence of oncogenic driver mutations in the Kirsten rat sarcoma viral oncogene homolog and epidermal growth factor receptor genes and to rearrangements in the anaplastic lymphoma kinase. Furthermore, activation of hypoxic signaling pathways and the transforming growth factor beta 1 axis can have an impact on the level of PD-L1 expression in NSCLC. A deeper understanding of the complex mechanisms regulating PD-L1 expression is necessary to tailor the treatment with ICI in patients with advanced NSCLC. PURPOSE: In this review, we present an overview of key factors underlying the regulation of PD-L1 expression within the TME of NSCLC, which are, and potentially can be, exploited to improve the outcomes of immunotherapy targeting the PD-1 axis.

Defining sex differences in selected lipid metabolites of blood plasma in Wistar rats.

There is an increasing attention to the role that sex/gender plays in health, behavior and outcomes. Even though we know that males and females are not the same, experiments have sometimes been carried out without considering sex in scientific research. It is essential for scientists and clinicians to consider sex differences as one of the underlying physiological determinants of health and disease to provide the building blocks for evidence-based, individualized medicine. Our work aimed to reveal sex-associated differences in lipid metabolite levels of adult female (n = 10) and male (n = 10) Wistar rats, aged 60 days. Partial least square determination analysis (PLS-DA) method and a variance importance in projection (VIP) score was used to identify the key sex-specific metabolites. Our results show that all groups of lipid metabolites: lysophosphatidylcholines (lysoPCs), phosphatidylcholines (PCs), and sphingomyelins (SMs) show a significant sex-dependent pattern. According to our results, more than a half of lysoPCs studied showed sex-specific features. PCs and lysoPCs tend to be significantly elevated in the blood plasma of females. The most distinct increase in more than 90% of SMs has been revealed in female blood plasma, compared with males. According to VIP score, the most important feature was the metabolite PC aa C38:4. Our study points out a sex dimorphism in lipid metabolism. The identification of main lipid features may play a key role in preclinical and clinical practice.