T. Merlinsky, J. Rahman, W. T. Johnson, L. McGary, S. Grassmann, J. Zhang, A. Abdulraouf, H. L. Kalvin, K. Panageas, J. Nicodemus, E. Cathcart, Y.-H. Lin, K. K. Hosszu, M. Berisa, O. Lyudovyk, G. Salles, J. J. Boelens, N. E. Babady, J. Cao, J. D. Wolchok, J. C. Sun, J. Heath, B. Greenbaum, S. Vardhana
N-acetylcysteine treatment improved clinical outcomes in cancer patients with steroid-refractory COVID-19. N-AC reduced circulating markers of innate inflammation, decreased MHC-II low monocytes, and increased CD8+ T cell abundance, activation, and effector differentiation. N-AC reduced the activity of inhibitory, redox sensitive transcription factors such as KLF6, enabling clonal expansion and effector T cell differentiation.
Severe COVID-19 infection in patients with cancer is characterized by a unique pattern of immunologic dysfunction including muted adaptive immune responses. The molecular drivers of immune dysfunction in cancer patients with severe COVID-19 remain unclear, and therapeutic strategies to overcome immune dysfunction in this setting have not been identified. We performed integrated proteomic and metabolomic profiling of matched cohorts of cancer and non-cancer patients with or without COVID-19 and identified dysfunctional cysteine metabolism as uniquely associated with severe COVID-19 in cancer patients. Treatment of patients with cancer and steroid-refractory COVID-19 with N-acetylcysteine in a prospective clinical trial (NCT04374461) improved clinical outcomes compared with disease severity-matched hospitalized patients during the period immediately preceding clinical trial initiation. N-AC treatment reduced circulating markers of innate inflammation, decreased severe disease-associated MHC-II low monocytes, and increased circulating CD8+ T cell abundance, activation, and effector differentiation. Mechanistically, N-AC reduced prostaglandin E2-driven interactions between suppressive monocytes and T cells, which we confirmed was sufficient to limit T cell expansion and effector differentiation in a dose- and avidity-dependent fashion. Moreover, N-AC reduced the activity of inhibitory, redox sensitive transcription factors such as KLF6, enabling clonal expansion and effector T cell differentiation. We confirmed these observations in two murine models of severe respiratory viral infection, in which N-AC treatment significantly enhanced lung-infiltrating CD8+ T cell abundance. These findings establish cysteine supplementation as a viable therapeutic strategy to reverse redox-driven immune dysregulation in severe respiratory viral infection, particularly in the high-risk cancer population.