ABSTRACT
Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC). Immune checkpoint inhibition (ICI) alone, and ICI in combination with chemotherapy, have demonstrated promising pathologic response (Subject(s)
Deoxycytidine
, Gemcitabine
, Immunotherapy
, Neoadjuvant Therapy
, Urinary Bladder Neoplasms
, Humans
, Urinary Bladder Neoplasms/drug therapy
, Urinary Bladder Neoplasms/immunology
, Urinary Bladder Neoplasms/therapy
, Urinary Bladder Neoplasms/pathology
, Neoadjuvant Therapy/methods
, Deoxycytidine/analogs & derivatives
, Deoxycytidine/therapeutic use
, Deoxycytidine/administration & dosage
, Immunotherapy/methods
, Male
, Cisplatin/therapeutic use
, Cisplatin/administration & dosage
, Female
, Antibodies, Monoclonal, Humanized/therapeutic use
, Antineoplastic Combined Chemotherapy Protocols/therapeutic use
, Immune Checkpoint Inhibitors/therapeutic use
, Aged
, Middle Aged
, Neoplasm Invasiveness
, Interleukin-9/metabolism
, B7-H1 Antigen/metabolism
, Biomarkers, Tumor/blood
, Treatment Outcome
ABSTRACT
In people with HIV (PWH), the post-antiretroviral therapy (ART) window is critical for immune restoration and HIV reservoir stabilization. We employ deep immune profiling and T cell receptor (TCR) sequencing and examine proliferation to assess how ART impacts T cell homeostasis. In PWH on long-term ART, lymphocyte frequencies and phenotypes are mostly stable. By contrast, broad phenotypic changes in natural killer (NK) cells, γδ T cells, B cells, and CD4+ and CD8+ T cells are observed in the post-ART window. Whereas CD8+ T cells mostly restore, memory CD4+ T subsets and cytolytic NK cells show incomplete restoration 1.4 years post ART. Surprisingly, the hierarchies and frequencies of dominant CD4 TCR clonotypes (0.1%-11% of all CD4+ T cells) remain stable post ART, suggesting that clonal homeostasis can be independent of homeostatic processes regulating CD4+ T cell absolute number, phenotypes, and function. The slow restoration of host immunity post ART also has implications for the design of ART interruption studies.