SARS-CoV-2 vaccination unmasks distinct immune dysfunctions across lymphoma subtypes and therapies.

Patients with lymphoma are at increased risk of severe infections, including SARS-CoV-2, due to immune suppression. Using multidimensional spectral flow cytometry and serology, we characterized in-depth immune responses in 50 SARS-CoV-2 vaccinated lymphoma patients across12 lymphoma subtypes, treated with anti-CD20 antibody (aCD20) ± chemotherapy (CT) or CT alone. Compared to healthy control, aCD20±CT-treated patients exhibited distinct immune alterations, including elevated late-stage effector memory (EM3) CD4+, and terminally differentiated (EMRA) CD8+ T cells, reduced circulating T follicular helper (cTfh) cells, and increased dysfunctional DN3 B cells. While B cell depletion was expected with aCD20 therapy, our data reveals broader immune dysregulation beyond B cell loss. Consistent with these phenotypic changes, aCD20±CT treated patients showed impaired vaccine-induced antibody and T-cell responses. In contrast, CT-only Hodgkin lymphoma patients maintained antibody responses comparable to healthy controls. Notably, SARS-CoV-2-specific T cells in aCD20±CT treated patients displayed fewer regulatory T cells, increased Th1 population, and more EMRA CD8+ T cells, suggesting a compensatory T-cell mediated immunity. Antibody response correlated positively with naïve T cell frequencies and transitional, classical memory, and DN2 B cell subsets. These findings inform the tailored development of vaccine strategies for immunocompromised patients to enhance protection against emerging SARS-CoV-2 variants and other viral pathogens.