Clonal amplification of peripheral CD4+ and CD8+ T cells is associated with clinical response to checkpoint blockade...

Therapeutic strategies for chronic hepatitis B (CHB) aim to achieve functional cure, specifically defined by sustained off-treatment elimination of hepatitis B virus (HBV) surface antigen. New treatment approaches are being developed to enhance HBV-specific immune responses to reach this goal. To better understand how checkpoint blockade works in CHB, we conducted single-cell sequencing analysis of blood samples from four patients who either responded or did not respond to a single dose of nivolumab (an anti-PD-1 therapy). We examined cells at baseline and at two subsequent timepoints during treatment. Our findings revealed that a patient who achieved functional cure displayed higher baseline levels of stem cell-like memory CD8+ T cells, along with increases in CD8+ T effector cells, CD8+ T effector memory cells, and CD4+ T cells that reexpress CD45RA at 24 weeks after nivolumab administration. Additionally, we observed the emergence of specific T and B cell clones during treatment that correlated with positive response. These clones were identified within CD8 T effector, CD8 T effector memory, CD4 T memory cells re-expressing CD45RA, and memory B cell populations. Notably, some prominent memory B cell clones had not undergone isotype switching, indicating the development of new B cell responses rather than modification of existing immune responses. These results suggest that certain T cell phenotypes in peripheral blood, together with specific clonal expansions of T and B cells, may indicate successful clinical response to checkpoint blockade therapy in CHB. Developing treatments that specifically enhance these immune mechanisms may lead to more effective therapeutic strategies.