Farhoud Faraji

T cells are major contributors to protective immunity against pathogens and cancers. Immune memory is a central feature of protective adaptive immunity, and mucosal barrier tissues are major sites of pathogen invasion. Yet, fundamental gaps remain in our knowledge of human T cell immune memory durability in mucosal barrier sites. Here, we employed minimally invasive nasal swab sampling to directly detect, and longitudinally assess, human antigen-specific T cells in two upper airway tissue sites (∼ 900 samples) and peripheral blood. Antigen-specific memory CD8 and CD4 T cells were detected in upper airway tissue of > 95% of individuals. Both memory CD8 and CD4 T cells were sustained in both mucosal epithelial and mucosal lymphoid tissue over the course of 18+ months, with monthly sampling, and no clear evidence of decline. Virus-specific upper airway CD8 and CD4 T cells were predominantly resident memory T cells (T _RM ) throughout the 18+ month period of observation. These findings can inform future T cell vaccines and therapeutics.

Background: Platelet‐rich plasma (PRP) has emerged as a promising therapy for post‐viral olfactory dysfunction (PVOD) though its biological mechanisms remain unclear. This study evaluated clinical outcomes and targeted proteomic changes following PRP for refractory PVOD. Methods: Adults with PVOD ≥ 6 months refractory to standard therapies underwent a single bilateral PRP injection into the olfactory clefts. Demographics, subjective olfactory ratings, and psychophysical assessment using the University of Pennsylvania Smell Identification Test (UPSIT) were obtained at baseline and follow‐up. Paired olfactory cleft mucus samples were analyzed using the Olink Target 48 immune panel, and baseline cytokine profiles were compared with normosmic controls. Results: Nineteen subjects were enrolled; 17 completed follow‐ups. The mean baseline UPSIT was 19 with a median PVOD duration of 27 months. At a mean follow‐up of 45 days, 47% reported subjective improvement and 53% achieved minimal clinically important difference. Mean UPSIT improved by +3.1 points (SD 6.0). Compared with controls, PVOD was associated with increased IL‐18 and CCL13 expression. Following PRP, paired comparisons demonstrated increased CSF2 and IL‐1β, and decreased IL‐6 and IL‐33. Pathway enrichment showed increased immune cell recruitment and tissue remodeling. Responders demonstrated increased oncostatin M (OSM) and a greater reduction in IL‐17F, with concurrent within‐subject increases in VEGFA and decreases in IL‐6 and IL‐33. Conclusion: PRP for refractory PVOD was associated with modest clinical improvement. Responder‐specific analyses suggest PRP may promote coordinated immune remodeling characterized by reduction of inflammatory and epithelial stress signaling and activation of reparative pathways. These findings support biological plausibility and warrant further investigation.

Seasonal influenza vaccines are most frequently delivered as intramuscular inactivated vaccines, which elicit systemic responses against the immunodominant hemagglutinin (HA) head domain. An intranasally administered, live-attenuated influenza vaccine designed to stimulate mucosal immunity, FluMist, is the sole intranasal vaccine approved in the United States. However, FluMist has lower systemic immunogenicity and efficacy in adults compared with intramuscular formulations. In this study, human mucosal and systemic immunity were examined after seasonal intramuscular or intranasal vaccination. Nasopharyngeal swabs of adenoid tissue were used to longitudinally sample the upper airway. FluMist induced substantial increases in upper respiratory tract IgG ⁺ and IgA ⁺ HA-specific memory B cells, which displayed an activated CD27 ⁺ CD21 ⁻ phenotype. H1, H3, and influenza B virus HA-specific memory B cells were all detected in the upper airway after intranasal immunization, remained elevated at 6 months postvaccination, and were associated with the presence of circulating T follicular helper (cT _FH ) cells. Recently activated upper airway memory B cells were not readily detected in intramuscular vaccinees, despite the elevation of systemic antibodies and circulating HA-specific memory B cells. Thus, despite minimal immune responses detected in circulation, adults vaccinated with the live-attenuated influenza vaccine generate substantial local antigen-specific memory B cell responses. These findings have implications for improving influenza vaccines and for mucosal vaccination against other respiratory pathogens.

Background: How anti-SARS-CoV-2 monoclonal antibodies (mAbs) change subsequent vaccine responses remains uncertain. Methods: We conducted a prospective, phase IV, open-label study of adults who received mRNA-1273 or BNT162b2. Cohort 1 included outpatients with acute COVID-19 previously randomized to mAbs (tixagevimab/cilgavimab or amubarvimab/romlusevimab), camostat, or placebo in ACTIV-2/A5401. Cohort 2 included unvaccinated adults without reported prior COVID-19 and was analyzed as naive or non-naive by baseline neutralizing antibodies (nAbs). We measured binding IgG, nAbs, spike-specific memory B cells, and CD4+/CD8+ T cells at baseline and days 28, 56, and 140. Results: Forty-three participants were analyzed. At day 140, nAb titers were lower among prior mAb recipients and COVID-19–naive participants than among placebo/camostat recipients and those with evidence of prior infection (overall P = .018). RBD-specific, but not spike-specific, memory B cells were reduced after prior mAb therapy at days 56 and 140. Frequency of spike-specific CD4 + and CD8+ T-cell responses did not differ by prior mAb exposure. Adverse events were mostly grade 1–2 and consistent with vaccine trials. Conclusions: Prior anti-SARS-CoV-2 mAb treatment limits endogenous RBD-focused B-cell responses to later mRNA vaccination without measurably affecting T-cell immunity. Timing of vaccination after mAb therapy may matter and warrants study. Clinical Trials Registration: NCT04952402.

Supplementary Figure 6. Squamous cell carcinoma (SCC)-positive tongues from the metformin + naproxen treatment arm. (Related to Figure 4)

Supplementary Figure 1. Genome-wide CRISPR-Cas9 screen identifies PKA signaling as a metformin resistance pathway in HNSCC. (Related to Figure 1)

Supplementary Figure 2. Activation of PKA in HNSCC cells reduces sensitivity to metformin growth inhibition in vivo. (Related to Figure 1)

Supplementary Figure 3. Combination of metformin with NSAIDs, which inhibit COX2, enhances the inhibition of HNSCC cell growth in vitro. (Related to Figure 3)