Intermittent MEK inhibition with GITR co-stimulation rescues T-cell function for increased efficacy with CTLA-4 blockade in solid tumor models.

MEK inhibitors (MEKis) have shown limited success as a treatment for MAPK/ERK pathway-dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds to MEK and prevents release of RAF, reducing the relief of negative feedback commonly observed with other MEKis. We observed that CKI27 increased MHC expression on tumor cells and improved T cell-mediated killing. Yet, CKI27 also decreased T-cell proliferation, activation, and cytolytic activity by inhibiting the MAPK/ERK pathway that is activated downstream of T cell-receptor signaling. Therefore, we aimed to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. Intermittent administration of CKI27 allowed T cells to partially recover and co-stimulation via GITR and OX-40 agonist antibodies completely alleviated inhibition of function. In Kras mutant lung and colon tumor mouse models, intermittent CKI27 and anti-GITR significantly decreased tumor growth and prolonged survival when further combined with CTLA-4 immune checkpoint blockade. Moreover, this triple combination increased CD8+ and CD4+ T-cell proliferation, activation, and effector/memory subsets in the tumor draining lymph nodes and tumors and led to intratumoral regulatory T cell (Treg) destabilization. These data, collectively, will allow for more informed decisions when optimizing combination regimens by overcoming resistance, reducing toxicity, and generating long-term immune responses.

Loss of circulating CD8α+ NK cells during human Mycobacterium tuberculosis infection.

Natural Killer (NK) cells can recognize and kill Mtb-infected cells in vitro, however their role after natural human exposure has not been well-studied. To identify Mtb-responsive NK cell populations, we analyzed the peripheral blood of healthy household contacts of active Tuberculosis (TB) cases and source community donors in an endemic region of Port-au-Prince, Haiti by flow cytometry. We observed higher CD8α expression on NK cells in putative resistors (IGRA- contacts) with a progressive loss of these circulating cells during household-associated latent infection and disease. In vitro assays and CITE-seq analysis of CD8α+ NK cells demonstrated enhanced maturity, cytotoxic gene expression, and response to cytokine stimulation relative to CD8α- NK cells. CD8α+ NK cells also displayed dynamic surface expression dependent on MHC I in contrast to conventional CD8+ T cells. Together, these results support a specialized role for CD8α+ NK cell populations during Mtb infection correlating with disease resistance.

Allergy-related disorders (ARDs) among Ethiopian primary school-aged children: Prevalence and associated risk factors.

BACKGROUND: There has been a noticeable increase in the prevalence of allergy-related disorders (ARDs) in the modern era. Urbanization is believed to be a major environmental risk factor for the onset of ARDs but data from low- to middle-income countries is limited. OBJECTIVE: Our purpose was to assess the prevalence of ARDs and atopy among a population of rural Ethiopian school children and identify environmental and lifestyle factors associated with such disorders. METHODS: We performed a cross-sectional study on 541 school-children. An interviewer-led questionnaire administered to the mothers of each participant provided information on demographic and lifestyle variables. Questions on allergic disease symptoms were based on the International Study of Asthma and Allergies in Children (ISAAC) core allergy and environmental questionnaire. Skin prick test for common allergens German cockroach (Blattella germanica) and dust mite (Dermatophagoides) was performed to define atopy. Multiple logistic regression analyses were performed to determine the odds ratio between ARDs and atopy with specific environmental and lifestyle habits. RESULTS: 541 children responded to the survey questions: the majority of participants were female (60.3%) and aged 10-15 years-old. The prevalence of any ARD was 27%, while the rates of ever-having eczema, rhinitis, and wheeze was found to be 16.8%, 9.6%, and 8.6% respectively. Only 3.6% (19 school-children) tested positive for any skin sensitization. Analysis of associated factors for ARDs found that a family history of allergic disorders (AOR: 2.80; p-value<0.01), use of insecticides (AOR: 2.05; p-value<0.01), and wearing open-toed shoes (AOR: 2.19; p-value = 0.02) were all significantly associated factors. Insecticide use, river-bathing, and infection with intestinal parasites were found to be significantly associated factors for atopy. Other potential risk factors such as frequent use of soap, bacterial infection, and household crowding had no statistical significance. CONCLUSION: Our study suggests that the prevalence of skin sensitization and ARDs in rural populations of developing countries is still relatively low. We identified several possible risk factors for further investigation. Overall, the significance of identified risk factors appears to indicate that genetic predisposition and exposure to environmental pollution are more important to the etiology of ARDs and atopy than specific lifestyle behaviors.