Doubling up on supersymmetry in the Higgs sector

We explore the possibility that physics at the TeV scale possesses approximate N =2 supersymmetry, which is reduced to the N =1 minimal supersymmetric extension of the Standard Model (MSSM) at the electroweak scale. This doubling of supersymmetry modifies the Higgs sector of the theory, with consequences for the masses, mixings and couplings of the MSSM Higgs bosons, whose phenomenological consequences we explore in this paper. The mass of the lightest neutral Higgs boson h is independent of tan β at the tree level, and the decoupling limit is realized whatever the values of the heavy Higgs boson masses. Radiative corrections to the top quark and stop squarks dominate over those due to particles in N = 2 gauge multiplets. We assume that these radiative corrections fix mh ≃ 125 GeV, whatever the masses of the other neutral Higgs bosons H, A, a scenario that we term the h2MSSM. Since the H, A bosons decouple from the W and Z bosons in the h2MSSM at tree level, only the LHC constraints on H, A and H± couplings to fermions are applicable. These and the indirect constraints from LHC measurements of h couplings are consistent with mA ≳ 200 GeV for tan β ∈ (2, 8) in the h2MSSM

Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment

Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development. Experimental cancer immunology and therap

Targeting of preexisting and induced breast cancer stem cells with trastuzumab and trastuzumab emtansine (T-DM1)

The antibody trastuzumab (Herceptin) has substantially improved overall survival for patients with aggressive HER2-positive breast cancer. However, about 70% of all treated patients will experience relapse or disease progression. This may be related to an insufficient targeting of the CD44(high)CD24(low) breast cancer stem cell subset, which is not only highly resistant to chemotherapy and radiotherapy but also a poor target for trastuzumab due to low HER2 surface expression. Hence, we explored whether the new antibody-drug conjugate T-DM1, which consists of the potent chemotherapeutic DM1 coupled to trastuzumab, could improve the targeting of these tumor-initiating or metastasis-initiating cells. To this aim, primary HER2-overexpressing tumor cells as well as HER2-positive and HER2-negative breast cancer cell lines were treated with T-DM1, and effects on survival, colony formation, gene and protein expression as well as antibody internalization were assessed. This revealed that CD44(high)CD24(low)HER2(low) stem cell-like breast cancer cells show high endocytic activity and are thus particularly sensitive towards the antibody-drug conjugate T-DM1. Consequently, preexisting CD44(high)CD24(low) cancer stem cells were depleted by concentrations of T-DM1 that did not affect the bulk of the tumor cells. Likewise, colony formation was efficiently suppressed. Moreover, when tumor cells were cocultured with natural killer cells, antibody-dependent cell-mediated cytotoxicity was enhanced, and EMT-mediated induction of stem cell-like properties was prevented in differentiated tumor cells. Thus our study reveals an unanticipated targeting of stem cell-like breast cancer cells by T-DM1 that may contribute to the clinical efficacy of this recently approved antibody-drug conjugate