Tumor-associated NK cells drive MDSC-mediated tumor immune tolerance through the IL-6/STAT3 axis.

Apart from their killer identity, natural killer (NK) cells have integral roles in shaping the tumor microenvironment. Through immune gene deconvolution, the present study revealed an interplay between NK cells and myeloid-derived suppressor cells (MDSCs) in nonresponders of immune checkpoint therapy. Given that the mechanisms governing the outcome of NK cell-to-myeloid cell interactions remain largely unknown, we sought to investigate the cross-talk between NK cells and suppressive myeloid cells. Upon contact with tumor-experienced NK cells, monocytes and neutrophils displayed increased expression of MDSC-related suppressive factors along with increased capacities to suppress T cells. These changes were accompanied by impaired antigen presentation by monocytes and increased ER stress response by neutrophils. In a cohort of patients with sarcoma and breast cancer, the production of interleukin-6 (IL-6) by tumor-infiltrating NK cells correlated with S100A8/9 and arginase-1 expression by MDSCs. At the same time, NK cell-derived IL-6 was associated with tumors with higher major histocompatibility complex class I expression, which we further validated with b2m-knockout (KO) tumor mice models. Similarly in syngeneic wild-type and IL-6 KO mouse models, we then demonstrated that the accumulation of MDSCs was influenced by the presence of such regulatory NK cells. Inhibition of the IL-6/signal transducer and activator of transcription 3 (STAT3) axis alleviated suppression of T cell responses, resulting in reduced tumor growth and metastatic dissemination. Together, these results characterize a critical NK cell-mediated mechanism that drives the development of MDSCs during tumor immune escape.

Unravelling the role of obesity and lipids during tumor progression.

The dysregulation of the biochemical pathways in cancer promotes oncogenic transformations and metastatic potential. Recent studies have shed light on how obesity and altered lipid metabolism could be the driving force for tumor progression. Here, in this review, we focus on liver cancer and discuss how obesity and lipid-driven metabolic reprogramming affect tumor, immune, and stroma cells in the tumor microenvironment and, in turn, how alterations in these cells synergize to influence and contribute to tumor growth and dissemination. With increasing evidence on how obesity exacerbates inflammation and immune tolerance, we also touch upon the impact of obesity and altered lipid metabolism on tumor immune escape.

Exploring the Allosteric Territory of Protein Function.

While the pervasiveness of allostery in proteins is commonly accepted, we further show the generic nature of allosteric mechanisms by analyzing here transmembrane ion-channel viroporin 3a and RNA-dependent RNA polymerase (RdRp) from SARS-CoV-2 along with metabolic enzymes isocitrate dehydrogenase 1 (IDH1) and fumarate hydratase (FH) implicated in cancers. Using the previously developed structure-based statistical mechanical model of allostery (SBSMMA), we share our experience in analyzing the allosteric signaling, predicting latent allosteric sites, inducing and tuning targeted allosteric response, and exploring the allosteric effects of mutations. This, yet incomplete list of phenomenology, forms a complex and unique allosteric territory of protein function, which should be thoroughly explored. We propose a generic computational framework, which not only allows one to obtain a comprehensive allosteric control over proteins but also provides an opportunity to approach the fragment-based design of allosteric effectors and drug candidates. The advantages of allosteric drugs over traditional orthosteric compounds, complemented by the emerging role of the allosteric effects of mutations in the expansion of the cancer mutational landscape and in the increased mutability of viral proteins, leave no choice besides further extensive studies of allosteric mechanisms and their biomedical implications.