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The role of ICB in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is not established. To gain insights into its potential in NLPHL, we compared TME and peripheral blood signatures between HLs using an integrative multiomic analysis. A discovery\/validation approach in 121 NLPHL and 114 cHL patients highlighted &gt;2\u2010fold enrichment in programmed cell death\u20101 (PD\u20101) and T\u2010cell Ig and ITIM domain (TIGIT) gene expression for NLPHL versus cHL. Multiplex imaging showed marked increase in intra\u2010tumoral protein expression of PD\u20101+ (and\/or TIGIT+) CD4+ T\u2010cells and PD\u20101+CD8+ T\u2010cells in NLPHL compared to cHL. This included T\u2010cells that rosetted with lymphocyte predominant (LP) and Hodgkin Reed\u2013Sternberg (HRS) cells. In NLPHL, intra\u2010tumoral PD\u20101+CD4+ T\u2010cells frequently expressed TCF\u20101, a marker of heightened T\u2010cell response to ICB. The peripheral blood signatures between HLs were also distinct, with higher levels of PD\u20101+TIGIT+ in TH1, TH2, and regulatory CD4+ T\u2010cells in NLPHL versus cHL. Circulating PD\u20101+CD4+ had high levels of TCF\u20101. Notably, in both lymphomas, highly expanded populations of clonal TIGIT+PD\u20101+CD4+ and TIGIT+PD\u20101+CD8+ T\u2010cells in the blood were also present in the TME, indicating that immune\u2010checkpoint expressing T\u2010cells circulated between intra\u2010tumoral and blood compartments. In <jats:italic>in vitro<\/jats:italic> assays, ICB was capable of reducing rosette formation around LP and HRS cells, suggesting that disruption of rosetting may be a mechanism of action of ICB in HL. Overall, results indicate that further evaluation of ICB is warranted in NLPHL.<\/jats:p>","DOI":"10.1002\/ajh.27459","type":"journal-article","created":{"date-parts":[[2024,8,17]],"date-time":"2024-08-17T09:42:47Z","timestamp":1723887767000},"page":"2096-2107","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Intra\u2010tumoral and peripheral blood <scp>TIGIT<\/scp> and <scp>PD<\/scp>\u20101 as immune biomarkers in nodular lymphocyte predominant Hodgkin lymphoma"],"prefix":"10.1002","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2695-3849","authenticated-orcid":false,"given":"Jay","family":"Gunawardana","sequence":"first","affiliation":[{"name":"Blood Cancer Research Group, Mater Research, Translational Research Institute University of Queensland  Brisbane Queensland 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