NKG2D is an important immunoreceptor expressed on the surface of NK cells and some T cells. NKG2D recognizes a set of ligands typically expressed on infected or transformed cells, but recent studies have also documented NKG2D ligands on subsets of host non-tumor cells in tumor-bearing animals and humans. Here we show that in transplanted tumors and genetically engineered mouse cancer models, tumor-associated macrophages are induced to express the NKG2D ligand RAE-1δ. We find that a soluble factor produced by tumor cells is responsible for macrophage RAE-1δ induction, and we identify tumor-derived colony-stimulating factor-1 (CSF-1) as necessary and sufficient for macrophage RAE-1δ induction in vitro and in vivo. Furthermore, we show that induction of RAE-1δ on macrophages by CSF-1 requires PI3K p110α kinase signaling. Thus, production of CSF-1 by tumor cells leading to activation of PI3K p110α represents a novel cellular and molecular pathway mediating NKG2D ligand expression on tumor-associated macrophages.

Natural Killer (NK) cells confer protection from tumors and infections by releasing cytotoxic granules and pro-inflammatory cytokines upon recognition of diseased cells. The responsiveness of NK cells to acute stimulation is dynamically tuned by steady-state receptor-ligand interactions of an NK cell with its cellular environment. Here, we demonstrate that in healthy WT mice the NK activating receptor NKG2D is engaged in vivo by one of its ligands, RAE-1ε, which is expressed constitutively by lymph node endothelial cells and highly induced on tumor-associated endothelium. This interaction causes internalization of NKG2D from the NK cell surface and transmits an NK-intrinsic signal that desensitizes NK cell responses globally to acute stimulation, resulting in impaired NK antitumor responses in vivo.

BACKGROUND: Neurocysticercosis (NCC) is the most common parasitic infection of the central nervous system and is typically diagnosed through visualization of the cysts in the cerebral parenchyma by neuro-imaging. However, neuro-imaging may not detect extraparenchymal neurocysticercosis (EPNCC), which is a rare manifestation of the disease involving the subarachnoid, meningeal, and intraventricular spaces. We report 2 cases of extraparenchymal neurocysticercosis, and discuss the diagnostic challenges and management of this entity. METHODS: Two cases were identified through clinical records. RESULTS: Both patients had an insidious onset with slow progression of disease, and presented with papilledema and cerebrospinal fluid (CSF) eosinophilia. One case was diagnosed with spinal cord biopsy. The other was diagnosed with CSF serology and next-generation sequencing-based pathogen analysis. Both patients were treated with ventriculoperitoneal shunt, systemic antiparasitic agents, and immunosuppression. CONCLUSIONS: EPNCC is less common than parenchymal NCC. A high level of clinical suspicion is required given its rarity, long incubation period, and slow progression. Diagnosis and treatment can be challenging and requires a multidisciplinary approach.

Various cytokines have been evaluated as potential anticancer drugs; however, most cytokine trials have shown relatively low efficacy. Here, we found that treatments with IL-12 and IL-18 or with a mutant form of IL-2 (the "superkine" called H9) provided substantial therapeutic benefit for mice specifically bearing MHC class I-deficient tumors, but these treatments were ineffective for mice with matched MHC class I+ tumors. Cytokine efficacy was linked to the reversal of the anergic state of NK cells that specifically occurred in MHC class I-deficient tumors, but not MHC class I+ tumors. NK cell anergy was accompanied by impaired early signal transduction and was locally imparted by the presence of MHC class I-deficient tumor cells, even when such cells were a minor population in a tumor mixture. These results demonstrate that MHC class I-deficient tumor cells can escape from the immune response by functionally inactivating NK cells, and suggest cytokine-based immunotherapy as a potential strategy for MHC class I-deficient tumors. These results suggest that such cytokine therapies would be optimized by stratification of patients. Moreover, our results suggest that such treatments may be highly beneficial in the context of therapies to enhance NK cell functions in cancer patients.

Background

In a placebo-controlled trial of the peptide-based therapeutic HIV-1 p24^Gag vaccine candidate Vacc-4x, participants on combination antiretroviral therapy (cART) received six immunizations over 18weeks, followed by analytical treatment interruption (ATI) between weeks 28 and 52. Cell-mediated immune responses were investigated as predictors of Vacc-4x effect (VE) on viral load (VL) and CD4 count during ATI.

Methods

All analyses of week 28 responses and fold-changes relative to baseline considered per-protocol participants (Vacc-4x:placebo=72:32) resuming cART after week 40. Linear regression models with interaction tests were used. VE was estimated as the Vacc-4x-placebo difference in log₁₀-transformed VL (VE^VL) or CD4 count (VE^CD4).

Findings

A lower fold-change of CD4+ T-cell proliferation was associated with VE^CD4 at week 48 (p=0.036, multiplicity adjusted q=0.036) and week 52 (p=0.040, q=0.080). A higher fold-change of IFN-γ in proliferation supernatants was associated with VE^VL at week 44 (p=0.047, q=0.07). A higher fold-change of TNF-α was associated with VE^VL at week 44 (p=0.045, q=0.070), week 48 (p=0.028, q=0.070), and week 52 (p=0.037, q=0.074). A higher fold-change of IL-6 was associated with VE^VL at week 48 (p=0.017, q=0.036). TNF-α levels (>median) were associated with VE^CD4 at week 48 (p=0.009, q=0.009).

Interpretation

These exploratory analyses highlight the potential value of investigating biomarkers in T-cell proliferation supernatants for VE in clinical studies.

Natural Killer (NK) cells confer protection from tumors and infections by releasing cytotoxic granules and pro-inflammatory cytokines upon recognition of diseased cells. The responsiveness of NK cells to acute stimulation is dynamically tuned by steady-state receptor-ligand interactions of an NK cell with its cellular environment. Here, we demonstrate that in healthy WT mice the NK activating receptor NKG2D is engaged in vivo by one of its ligands, RAE-1ε, which is expressed constitutively by lymph node endothelial cells and highly induced on tumor-associated endothelium. This interaction causes internalization of NKG2D from the NK cell surface and transmits an NK-intrinsic signal that desensitizes NK cell responses globally to acute stimulation, resulting in impaired NK antitumor responses in vivo.

NKG2D is an important immunoreceptor expressed on the surface of NK cells and some T cells. NKG2D recognizes a set of ligands typically expressed on infected or transformed cells, but recent studies have also documented NKG2D ligands on subsets of host non-tumor cells in tumor-bearing animals and humans. Here we show that in transplanted tumors and genetically engineered mouse cancer models, tumor-associated macrophages are induced to express the NKG2D ligand RAE-1δ. We find that a soluble factor produced by tumor cells is responsible for macrophage RAE-1δ induction, and we identify tumor-derived colony-stimulating factor-1 (CSF-1) as necessary and sufficient for macrophage RAE-1δ induction in vitro and in vivo. Furthermore, we show that induction of RAE-1δ on macrophages by CSF-1 requires PI3K p110α kinase signaling. Thus, production of CSF-1 by tumor cells leading to activation of PI3K p110α represents a novel cellular and molecular pathway mediating NKG2D ligand expression on tumor-associated macrophages.

Background

The COVID-19 pandemic increased disparities for communities burdened by structural barriers such as reduced affordable housing, with mental health consequences. Limited data are available on digital resources for public mental health prevention during the COVID-19 pandemic.

Objective

The study aim was to evaluate engagement in and impact of free digital resources on the Together for Wellness/Juntos por Nuestro Bienestar (T4W/Juntos) website during COVID-19 in California.

Methods

A pilot evaluation of T4W/Juntos was performed, with partner agencies inviting providers, clients, and partners to visit the website and complete surveys at baseline (September 20, 2021, to April 4, 2022) and at 4-6-week follow-up (October 22, 2021, to May 17, 2022). Website use was assessed by three engagement items (ease of use, satisfaction, relevance), comfort in use, and use of six resource categories. Primary outcomes at follow-up were depression and anxiety (scores≥3 on Patient Health Questionnaire-2 item [PHQ2] and Generalized Anxiety Disorder-2 item [GAD2] scales). Secondary outcomes were post-pre differences in PHQ2 and GAD2 scores, and use of behavioral health hotlines and services the month before follow-up.

Results

Of 366 eligible participants, 315 (86.1%) completed baseline and 193 (61.3%) completed follow-up surveys. Of baseline participants, 72.6% identified as female, and 21.3% identified as lesbian, gay, bisexual, transgender, queer/questioning, and others (LGBTQ+). In terms of ethnicity, 44.0% identified as Hispanic, 17.8% as African American, 26.9% as non-Hispanic white, and 11.4% as other ethnicity. Overall, 32.7% had moderate anxiety or depression (GAD2/PHQ2≥3) at baseline. Predictors of baseline website engagement included being Hispanic versus other race/ethnicity (β=.27, 95% CI .10-.44; P=.002) and number of COVID-19-related behavior changes (β=.09, 95% CI .05-.13; P<.001). Predictors of comfort using the website were preferring English for website use (odds ratio [OR] 5.57, 95% CI 2.22-13.96; P<.001) and COVID-19-related behavior changes (OR 1.37, 95% CI 1.12-1.66; P=.002); receiving overnight behavioral health treatment in the prior 6 months (OR 0.15, 95% CI 0.03-0.69, P=.015) was associated with less comfort in website use. The main predictor of depression at follow-up (PHQ2≥3) was baseline depression (OR 6.24, 95% CI 2.77-14.09; P<.001). Engagement in T4W/Juntos was associated with lower likelihood of depression (OR 0.54, 95% CI 0.34-0.86; P=.01). Website use the month before follow-up was associated with a post-pre reduction in PHQ2 score (β=-.62, 95% CI -1.04 to -0.20; P=.004). The main predictor of GAD2≥3 at follow-up was baseline GAD2≥3 (OR 13.65, 95% CI 6.06-30.72; P<.001). Greater baseline website engagement predicted reduced hotline use (OR 0.36, 95% CI 0.18-0.71; P=.004).

Conclusions

Ethnicity/language and COVID-19-related behavior changes were associated with website engagement; engagement and use predicted reduced follow-up depression and behavioral hotline use. Findings are based on participants recommended by community agencies with moderate follow-up rates; however, significance was similar when weighting for nonresponse. This study may inform research and policy on digital mental health prevention resources.

This paper explores the effects of a group-randomized controlled trial, Community Partners in Care (CPIC), on the development of interagency networks for collaborative depression care improvement between a community engagement and planning (CEP) intervention and a resources for services (RS) intervention that provided the same content solely via technical assistance to individual programs. Both interventions consisted of a diverse set of service agencies, including health, mental health, substance abuse treatment, social services, and community-trusted organizations such as churches and parks and recreation centers. Participants in the community councils for the CEP intervention reflected a range of agency leaders, staff, and other stakeholders. Network analysis of partnerships among agencies in the CEP versus RS condition, and qualitative analysis of perspectives on interagency network changes from multiple sources, suggested that agencies in the CEP intervention exhibited greater growth in partnership capacity among themselves than did RS agencies. CEP participants also viewed the coalition development intervention both as promoting collaboration in depression services and as a meaningful community capacity building activity. These descriptive results help to identify plausible mechanisms of action for the CPIC interventions and can be used to guide development of future community engagement interventions and evaluations in under-resourced communities.

Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.