Immune checkpoint blockade, exemplified by antibodies targeting the PD-1 receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T-cell activation, contributing to antitumor effects in vivo, due in part to the derepression of NFAT family proteins and their target genes, critical regulators of T-cell function. Although CDK4/6 inhibitors decrease T-cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel ex vivo organotypic tumor spheroid culture system and in multiple in vivo murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies. Significance: Our results define previously unrecognized immunomodulatory functions of CDK4/6 and suggest that combining CDK4/6 inhibitors with immune checkpoint blockade may increase treatment efficacy in patients. Furthermore, our study highlights the critical importance of identifying complementary strategies to improve the efficacy of immunotherapy for patients with cancer. Cancer Discov; 8(2); 216–33. ©2017 AACR. See related commentary by Balko and Sosman, p. 143. See related article by Jenkins et al., p. 196. This article is highlighted in the In This Issue feature, p. 127

Fluorescent dyes which are specific for duplex DNA have found a wide range of applications from staining gels to visualization of chromosomes. Porphyrin dyes have been found which are highly fluorescent in the presence of quadruplex but not duplex DNA. These dyes may offer a route to the specific detection of quadruplex DNA under biologically important conditions. There are three types of DNA quadruplex structures, and these may play important roles in telomere, centromere, triplet repeat, integration sites and other DNAs, and this first set of porphyrin dyes show some selectivity between the quadruplex types.

Many key aspects of control of quantum systems involve manipulating a large quantum ensemble exhibiting variation in the value of parameters characterizing the system dynamics. Developing electromagnetic pulses to produce a desired evolution in the presence of such variation is a fundamental and challenging problem in this research area. We present such robust pulse designs as an optimal control problem of a continuum of bilinear systems with a common control function. We map this control problem of infinite dimension to a problem of polynomial approximation employing tools from geometric control theory. We then adopt this new notion and develop a unified computational method for optimal pulse design using ideas from pseudospectral approximations, by which a continuous-time optimal control problem of pulse design can be discretized to a constrained optimization problem with spectral accuracy. Furthermore, this is a highly flexible and efficient numerical method that requires low order of discretization and yields inherently smooth solutions. We demonstrate this method by designing effective broadband π /2 and π pulses with reduced rf energy and pulse duration, which show significant sensitivity enhancement at the edge of the spectrum over conventional pulses in 1D and 2D NMR spectroscopy experiments.