Neem Leaf Glycoprotein disrupts exhausted CD8+ T cell-mediated cancer stem cell aggression.

Targeting exhausted CD8+T cell (TEX) induced aggravated cancer stem cells (CSC) holds immense therapeutic potential. In this regard, immunomodulation via Neem Leaf Glycoprotein (NLGP), a plant-derived glycoprotein immunomodulator is explored. Since former reports have proven immune-dependent tumor restriction of NLGP across multiple tumor models, we hypothesized that NLGP might reprogram and rectify TEX to target CSCs successfully. Here we report that NLGP's therapeutic administration significantly reduced TEX -associated CSC virulence in in vivo B16-F10 melanoma tumor model. Similar trend was observed in in vitro generated TEX and B16-F10/MCF7 co-culture setups. NLGP rewired CSCs by downregulating clonogenicity, multidrug resistance phenotypes and PDL1, OCT4, SOX2 expression. Cell cycle analysis revealed that NLGP-educated TEX efficiently pushed CSCs out of quiescent-phase (G0G1) into synthesis-phase (S), supported by hyper-phosphorylation of G0G1-S transitory cyclins and Rb-proteins. This rendered quiescent CSCs susceptible to s-phase targeting chemotherapeutic drugs like 5-Fluorouracil (5FU). Consequently combinatorial treatment of NLGP and 5FU brought optimal CSC targeting efficiency with increase in apoptotic bodies and pro-apoptotic BID expression. Notably a strong nephron-protective effect of NLGP was also observed, which prevented 5FU associated toxicity. Furthermore, Dectin-1 mediated NLGP uptake and subsequent alteration of Notch1 and mTOR axis was deciphered as the involved signalling network. This observation unveiled Dectin-1 as a potent immunotherapeutic drug-target to counter T cell exhaustion. Cumulatively, NLGP immunotherapy alleviated exhausted CD8+T cell induced CSC aggravation. Implications: Our study recommends that NLGP-immunotherapy can be utilized to counter ramifications of T cell exhaustion and to target therapy elusive aggressive CSCs without evoking toxicity.

Cancer stem cell-immune cell crosstalk in breast tumor microenvironment: a determinant of therapeutic facet.

Breast cancer (BC) is globally one of the leading killers among women. Within a breast tumor, a minor population of transformed cells accountable for drug resistance, survival, and metastasis is known as breast cancer stem cells (BCSCs). Several experimental lines of evidence have indicated that BCSCs influence the functionality of immune cells. They evade immune surveillance by altering the characteristics of immune cells and modulate the tumor landscape to an immune-suppressive type. They are proficient in switching from a quiescent phase (slowly cycling) to an actively proliferating phenotype with a high degree of plasticity. This review confers the relevance and impact of crosstalk between immune cells and BCSCs as a fate determinant for BC prognosis. It also focuses on current strategies for targeting these aberrant BCSCs that could open avenues for the treatment of breast carcinoma.

Tumor activated platelets induce vascular mimicry in mesenchymal stem cells and aid metastasis.

Extent of metastasis influences activation of platelets in tumor-microenvironment. Activated platelets potentiate mesenchymal-stem-cells (MSCs) to migrate in secondary metastatic sites without participation in process of invasion. Presence of higher percentage of MSCs along with activated-platelets induces formation of vascular-mimicry (VM). The pathophysiology, VM, has already been reported in multiple types of cancer including lung, ovary, melanoma etc. and related to poor-prognosis. Interaction of MSCs with platelets in cell-to-cell contact dependent manner is essential for their migration, thereby, VM. Evidences are obtained suggesting that under influence of tumor-associated-activated-platelets, expressions of vimentin, ve-cadherin are increased, along with decrease in e-cadherin on CD105+ MSCs in both mRNA and protein levels that may help in formation of vessel like structure in VM. Adoptive transfer of MSCs along with tumor-activated-platelets causes greater B16 melanoma metastasis at lungs in comparison to MSCs with non-activated platelets. Presence of CD105+Vimentin+ MSCs in vessel like structure in the metastatic lung confirms the involvement of platelet-activated-MSCs in VM, thereby, in metastasis.