Human KLRG1 blocking peptide

OX40 is a costimulatory receptor that potentiates proliferation, survival, memory formation, and effector function of CD4(+) and CD8(+) T-cells, while overcoming the suppressive activity of regulatory T-cells (Tregs). Here, we explored the combination of an OX40L fusion protein (OX40L-FP) with a poxvirus-based cancer vaccine (MVA-Twist-TRICOM) to inhibit tumor metastasis in the 4T1 murine breast cancer model. Contrary to the single agent treatments, the combination therapy significantly decreased the number of metastatic colonies per lung and prolonged survival. Depletion studies demonstrated that these effects were mediated by both CD4(+) and CD8(+) T-cells. The combination therapy a) increased the total number of T-cells in the CD4(+) Foxp3-population and the CD4(+) central and effector memory subsets within the lung, spleen, and draining lymph node, b) enhanced infiltration of CD4(+) T-cells into metastatic areas of the lung, and (c) increased the number of functional CD8(+) T-cells that produced IFN gamma and TNF alpha. The combination therapy also promoted the development of KLRG1-CD127(+) memory precursor CD8(+) T-cells, while reducing those with a KLRG1(+) terminally differentiated phenotype. Moreover, the combination of OX40L-FP and vaccine induced greater CD4(+) and CD8(+) Twist-specific responses. In addition, Tregs isolated from mice receiving the combination were also less immunosuppressive in ex-vivo proliferation assays than those from the OX40L-FP and MVA-Twist-TRICOM monotherapy groups. Such results provide the rationale to combine co-stimulatory agonists with cancer vaccines for the treatment of tumor metastasis.

Didecyldimethylammonium chloride (DDAC) is an antimicrobial dialkyl-quaternary ammonium compound used in industrial and commercial products. Clinical data suggest that DDAC exposure elicits multiple types of hypersensitivity reactions; here, we confirm this observation in a BALB/c murine model. To examine the immunological mechanism behind this mixed-type response and the potential involvement of type 2 innate lymphoid cells (ILC2s), we assessed early immune responses in the skin following topical DDAC exposure (0.125% and 0.5%). DDAC exposure resulted in a rapid and dramatic increase in the Th2-skewing and ILC2-activating cytokine thymic stromal lymphopoietin. Correspondingly, dermal ILC2s were activated 24h after DDAC exposure, resulting in increased expression of CD25, ICOS and KLRG1, and decreased CD127 throughout 7days of exposure. Following ILC2 activation, the Th2 cytokine IL-4 was elevated compared with control mice in total ear protein lysate (0.5% DDAC). Rag2(-/-) mice were used to determine a functional role for ILC2s in DDAC-induced sensitization. ILC2s from Rag2(-/-) mice were similarly activated by DDAC and, importantly, produced significant levels of IL-4 and IL-5 in the skin (0.5% DDAC). These data indicate that ILC2s contribute to early Th2 immune responses following DDAC exposure. ILC2s have been previously implicated in allergic responses, but to our knowledge have not been thoroughly investigated in chemical sensitization. These results indicate that following DDAC exposure, skin ILC2s become activated and produce Th2 cytokines, providing a possible mechanism for the development of the mixed-type allergic responses commonly observed with chemical sensitizers.