Expression of modified FcγRI enables myeloid cells to elicit robust tumor-specific cytotoxicity.

Despite the central role of T cells in tumor immunity, attempts to harness their cytotoxic capacity as a therapy have met limited efficacy, partially as a result of the suppressive microenvironment which limits their migration and activation. In contrast, myeloid cells massively infiltrate tumors and are well adapted to survive these harsh conditions. While they are equipped with cell-killing abilities, they often adopt an immunosuppressive phenotype upon migration to tumors. Therefore, the questions of how to modify their activation programming against cancer, and what signaling cascades should be activated in myeloid cells to elicit their cytotoxicity have remained unclear. Here, we found that activation of IgM-induced signaling in murine myeloid cells results in secretion of lytic granules and massive tumor cell death. These findings open venues for designing novel immunotherapy by equipping monocytes with chimeric receptors that target tumor antigens and consequently, signal through IgM receptor. Nonetheless, we found that myeloid cells do not express the antibody-derived portion used to recognize the tumor antigen due to the induction of an ER stress response. To overcome this limitation, we designed chimeric receptors that are based on the high-affinity FcγRI for IgG. Incubation of macrophages expressing these receptors along with tumor-binding IgG induced massive tumor cell killing and secretion of reactive oxygen species and Granzyme B. Overall, this work highlights the challenges involved in genetically reprogramming the signaling in myeloid cells and provides a framework for endowing myeloid cells with antigen-specific cytotoxicity.

Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy.

T cell inhibitory mechanisms prevent autoimmune reactions, while cancer immunotherapy aims to remove these inhibitory signals. Chronic ultraviolet (UV) exposure attenuates autoimmunity through promotion of poorly understood immune-suppressive mechanisms. Here we show that mice with subcutaneous melanoma are not responsive to anti-PD1 immunotherapy following chronic UV irradiation, given prior to tumor injection, due to the suppression of T cell killing ability in skin-draining lymph nodes. Using mass cytometry and single-cell RNA-sequencing analyzes, we discover that skin-specific, UV-induced suppression of T-cells killing activity is mediated by upregulation of a Ly6ahigh T-cell subpopulation. Independently of the UV effect, Ly6ahigh T cells are induced by chronic type-1 interferon in the tumor microenvironment. Treatment with an anti-Ly6a antibody enhances the anti-tumoral cytotoxic activity of T cells and reprograms their mitochondrial metabolism via the Erk/cMyc axis. Treatment with an anti-Ly6a antibody inhibits tumor growth in mice resistant to anti-PD1 therapy. Applying our findings in humans could lead to an immunotherapy treatment for patients with resistance to existing treatments.

Cognitive state, substance use patterns and outcome after discharge from Kfar Izun, a unique rehabilitation facility.

We studied cognitive performance following discharge from a novel rehabilitation facility, treating individuals with psychosis that developed during trips abroad following mandatory military service. Montreal Cognitive Assessment (MoCA), phonetic and semantic fluency, State-Trait Anxiety, and self-Efficiency were administered before discharge, and 3 and 6 months after discharge. Of the 43 participants (30.2% females), 23(54.8%) had cognitive impairment (MoCA <27), and 15(35.7%) had poor phonetic fluency. Anxiety trait and state were high and inversely correlated with self-efficacy (R=-0.48, p = 0.001) and phonetic fluency (R=-0.43, p = 0.004) and was higher among those who experienced physical exposure, females, and those who served in non-combat army units. Six months after discharge, of 32 participants, 28 were working/studying with a 58.1% reduction in smoking and alcohol consumption, and 16 participants stopped substance use. Phonetic fluency improved among the high anxiety state group with no change among the others. High anxiety levels lowered among those who were still using drugs after six months. The anxiety level lowered and 87.1% of the participants were conducting a productive lifestyle at 6 months after discharge, but half still abused cannabis. Bigger sample and longer follow up would be needed to learn more about the impact of rehabilitation.