PD-1 and CTLA-4 serve as major gatekeepers for effector and cytotoxic T-cell potentiation by limiting a CXCL9/10-CXCR3-IFNγ positive feedback loop.

CXCR3 is a chemokine receptor with three ligands: CXCL9, CXCL10 and CXCL11. We report that in addition to attracting CXCR3+ T cells to tumor sites a key role of CXCL9 and CXCL10 is in inducing a self-feeding feedback loop that accelerates effector/cytotoxic activities of both CD4+ and CD8+ T cells while downregulating immunoregulatory protein TIM3. CXCR3KO mice displayed a markedly reduced response to anti-PD-1 and anti-CTLA-4 therapy.

Knock-Out of the Five Lysyl-Oxidase Family Genes Enables Identification of Lysyl-Oxidase Pro-Enzyme Regulated Genes.

The five lysyl-oxidase genes share similar enzymatic activities and contribute to tumor progression. We have knocked out the five lysyl-oxidase genes in MDA-MB-231 breast cancer cells using CRISPR/Cas9 in order to identify genes that are regulated by LOX but not by other lysyl-oxidases and in order to study such genes in more mechanistic detail in the future. Re-expression of the full-length cDNA encoding LOX identified four genes whose expression was downregulated in the knock-out cells and rescued following LOX re-expression but not re-expression of other lysyl-oxidases.

The role of CCR5 in directing the mobilization and biological function of CD11bGr1Ly6C polymorphonuclear myeloid cells in cancer.

Bone marrow (BM) cells of the hematopoietic system, also known as BM-derived leukocytes (BMD), are mobilized from the BM to the blood and then colonize tumor sites. These cells then become key players in either promoting or regulating the development and progression of tumors. Among the cells that suppress anti-tumor immunity are regulatory T cells (T), tumor-associated macrophages (TAMS) and myeloid-derived suppressor cells (MDSC).

Chemokines beyond chemo-attraction: CXCL10 and its significant role in cancer and autoimmunity.

Chemokines are mostly known for their chemotactic properties, and less for their ability to direct the biological function of target cells, including T cells. The current review focuses on a key chemokine named CXCL10 and its role in directing the migratory propertied and biological function of CD4+ and CD8+ T cells in the context of cancer and inflammatory autoimmunity. CXCR3 is a chemokine receptor that is abundant on CD4+ T cells, CD8+ T cells and NK cells.

CCR5 Directs the Mobilization of CD11bGr1Ly6C Polymorphonuclear Myeloid Cells from the Bone Marrow to the Blood to Support Tumor Development.

Cells of hematopoietic origin can be subdivided into cells of the lymphoid lineage and those of the myeloid lineage, among which are myeloid-derived suppressor cells (MDSCs). The MDSCs can be further divided into CD11bLy6GLy6C monocytic (Mo) MDSCs and CD11bLy6GLy6C polymorphonuclear (PMN) MDSCs. Both subtypes support tumor growth and suppress anti-tumor immunity.

CCR5 Myeloid-Derived Suppressor Cells Are Enriched and Activated in Melanoma Lesions.

Accumulation of myeloid-derived suppressor cells (MDSC) in melanoma microenvironment is supported by chemokine receptor/chemokine signaling. Although different chemokines were suggested to be involved in this process, the role of CCR5 and its ligands is not established. Using a transgenic mouse melanoma model, we found an accumulation of CCR5 MDSCs in melanoma lesions associated with both increased concentrations of CCR5 ligands and tumor progression.

Effect of alpha-naphthylisothiocyanate-induced liver injury on intestinal adaptation in a rat model of short bowel syndrome.

Background/purpose: Progressive hyperbilirubinemia and end-stage liver failure are among the most serious complications of short bowel syndrome (SBS), representing the principle cause of death in a majority of fatal cases. In the current study, we examined the effects of alpha-naphthylisothiocyanate (ANIT)-induced liver injury on intestinal adaptation in a rat model of SBS.

Methods: Male rats were divided into four groups: Sham rats underwent bowel transection (n = 8), Sham liver-injury rats underwent bowel transection and IP injection of ANIT (100 mg/kg, n = 8), SBS rats underwent a 75% bowel resection, and SBS-ANIT rats underwent bowel resection and liver injury similar to group sham-ANIT (n = 8).