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NK cells, lymphocytes of the innate immune system, are important for defense against infectious pathogens and cancer. Classically, the CD56dim NK cell subset is thought to mediate antitumor responses, whereas the CD56bright subset is involved in immunomodulation. Here, we challenge this paradigm by demonstrating that brief priming with IL-15 markedly enhanced the antitumor response of CD56bright NK cells. Priming improved multiple CD56bright cell functions: degranulation, cytotoxicity, and cytokine production. Primed CD56bright cells from leukemia patients demonstrated enhanced responses to autologous blasts in vitro, and primed CD56bright cells controlled leukemia cells in vivo in a murine xenograft model. Primed CD56bright cells from multiple myeloma (MM) patients displayed superior responses to autologous myeloma targets, and furthermore, CD56bright NK cells from MM patients primed with the IL-15 receptor agonist ALT-803 in vivo displayed enhanced ex vivo functional responses to MM targets. Effector mechanisms contributing to IL-15-based priming included improved cytotoxic protein expression, target cell conjugation, and LFA-1-, CD2-, and NKG2D-dependent activation of NK cells. Finally, IL-15 robustly stimulated the PI3K/Akt/mTOR and MEK/ERK pathways in CD56bright compared with CD56dim NK cells, and blockade of these pathways attenuated antitumor responses. These findings identify CD56bright NK cells as potent antitumor effectors that warrant further investigation as a cancer immunotherapy.

BackgroundThe COVID-19 pandemic drastically impacted medical student experiences. Little is known about the impact of the pandemic on student well-being and protective factors for burnout.ObjectiveAssess US medical student burnout, stress, and loneliness during the initial phase of the pandemic, compare results to pre-pandemic data, and identify risk factors for distress and protective factors to inform support interventions.DesignCross-sectional survey of medical students conducted between May and July 2020.Participants3826 students from 22 medical schools.Main MeasuresBurnout (MBI-HSS), stress (PSS-10), loneliness (UCLA scale), and student experiences. Compared burnout and stress to pre-pandemic studies (2010–2020).Key ResultsOf 12,389 students, 3826 responded (31%). Compared to pre-pandemic studies, burnout was lower (50% vs. 52%, P = 0.03) while mean stress was higher (18.9 vs. 16.0, P < 0.001). Half (1609/3247) reported high (≥ 6/9) loneliness scores. Significant differences were found in burnout and stress by class year (P = 0.002 and P < 0.001) and race (P = 0.004 and P < 0.001), with the highest levels in second- and third-year students and Black, Asian, or other racial minority students. Students experiencing financial strain or racism had higher burnout and stress (P < 0.001 for all). Respondents with COVID-19 diagnoses in themselves or family members had higher stress (P < 0.001). Nearly half (1756/3569) volunteered during the pandemic, with volunteers reporting lower burnout [48% (782/1639) vs. 52% (853/1656), P = 0.03].ConclusionsWhile stress was higher compared to pre-pandemic data, burnout was significantly lower. Higher burnout and stress among Black, Asian, and other racial minority students and those who experienced financial strain, racism, or COVID-19 diagnoses likely reflect underlying racial and socioeconomic inequalities exacerbated by the pandemic and concurrent national racial injustice events. Volunteer engagement may be protective against burnout. Schools should proactively support vulnerable students during periods of stress.

NK cells, lymphocytes of the innate immune system, are important for defense against infectious pathogens and cancer. Classically, the CD56dim NK cell subset is thought to mediate antitumor responses, whereas the CD56b,ightsubset is involved in immunomodulation. Here, we challenge this paradigm by demonstrating that brief priming with IL-15 markedly enhanced the antitumor response of CD56b'ight NK cells. Priming improved multiple CD56bright cell functions: degranulation, cytotoxicity, and cytokine production. Primed CD56b'ight cells from leukemia patients demonstrated enhanced responses to autologous blasts in vitro, and primed CD56bright cells controlled leukemia cells in vivo in a murine xenograft model. Primed CD56b'ight cells from multiple myeloma (MM) patients displayed superior responses to autologous myeloma targets, and furthermore, CD56b'ight NK cells from MM patients primed with the IL-15 receptor agonist ALT-803 in vivo displayed enhanced ex vivo functional responses to MM targets. Effector mechanisms contributing to IL-15-based priming included improved cytotoxic protein expression, target cell conjugation, and LFA-1-, CD2-, and NKG2D-dependent activation of NK cells. Finally, IL-15 robustly stimulated the PI3K/Akt/mTOR and MEK/ERK pathways in CD56b'ightcompared with CD56dim NK cells, and blockade of these pathways attenuated antitumor responses. These findings identify CD56bright NK cells as potent antitumor effectors that warrant further investigation as a cancer immunotherapy.

NK cells, lymphocytes of the innate immune system, are important for defense against infectious pathogens and cancer. Classically, the [CD56.sup.dim] NK cell subset is thought to mediate antitumor responses, whereas the [CD56.sup.bright] subset is involved in immunomodulation. Here, we challenge this paradigm by demonstrating that brief priming with IL-15 markedly enhanced the antitumor response of [CD56.sup.bright] NK cells. Priming improved multiple [CD56.sup.bright] cell functions: degranulation, cytotoxicity, and cytokine production. Primed [CD56.sup.bright] cells from leukemia patients demonstrated enhanced responses to autologous blasts in vitro, and primed [CD56.sup.bright] cells controlled leukemia cells in vivo in a murine xenograft model. Primed [CD56.sup.bright] cells from multiple myeloma (MM) patients displayed superior responses to autologous myeloma targets, and furthermore, CD56b'igl,t NK cells from MM patients primed with the IL-15 receptor agonist ALT-803 in vivo displayed enhanced ex vivo functional responses to MM targets. Effector mechanisms contributing to IL-15- based priming included improved cytotoxic protein expression, target cell conjugation, and LFA-1-, CD2-, and NKG2D- dependent activation of NK cells. Finally, IL-15 robustly stimulated the PI3K/Akt/mTOR and MEK/ERK pathways in [CD56.sup.bright] compared with [CD56.sup.dim] NK cells, and blockade of these pathways attenuated antitumor responses. These findings identify [CD56.sup.bright] NK cells as potent antitumor effectors that warrant further investigation as a cancer immunotherapy.