Abstract Over the last few years, we have gained insights into how immunotherapy, including checkpoint blockade, modulates key CD4 and CD8 T cell subsets in anti-tumor immunity. This information can now give us insights into how immunotherapy can impact immunity in the setting of COVID-19. Indeed, we recently demonstrated that cancer patients with T cell depletion have high COVID-19 mortality despite adequate B cell and antibody production, highlighting the importance of cellular immunity. Conversely, in the setting of B cell depletion by anti-CD20 therapy, CD8 T cells can compensate for impaired humoral immunity. PD-1 blockade increases the activation and proliferation of CD4 T follicular-helper cells, which plays a key role in promoting B cell responses and quality antibody production. Thus, it is possible that PD-1 blockade enhances the efficacy of SARS-CoV-2 vaccination. However, PD-1 blockade in melanoma patients was actually associated with at 2-fold decrease in SARS-CoV-2 specific antibodies and neutralizing antibodies, compared to a healthy donor cohort. PD-1 blockade was also associated with depletion of memory CD4 T cells, suggesting there may be consequences to prolonged PD-1 blockade. Citation Format: Paulina Coutifaris, Kevin Wang, Sokratis Apostolidis, Mark Painter, Ahron Flowers, Rishi Goel, Divij Mathew, Ajinkya Pattekar, Ravi Amaravadi, Tara Mitchell, Paul Bates, Scott Hensley, Giorgos Karakousis, Lynn Schuchter, Allie Greenplate, E. John Wherry, Alexander C. Huang. Impact of immunotherapy on COVID-19 immunity: Insights from checkpoint blockade in cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr IA07.