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Summary: Reliable biomarkers for early identification of treatment failure in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL) are lacking. Circulating tumour DNA (ctDNA) profiling has emerged as a powerful predictive and prognostic tool in several haemopoietic and non‐haemopoietic malignancies and may guide rational treatment choices in r/r cHL. To assess the predictive and prognostic value of ctDNA, we performed a retrospective analysis on 55 r/r cHL patients treated with the bendamustine, gemcitabine and vinorelbine (BEGEV) regimen and additionally evaluated the potential utility of integrating ctDNA with interim [18F]‐FDG positron emission tomography (iPET). Baseline ctDNA genotyping in r/r cHL mirrored gene mutations and pathways involved in newly diagnosed cHL. We found that baseline ctDNA quantification and serial ctDNA monitoring have prognostic value in r/r cHL receiving salvage chemotherapy. Lastly, integrating ctDNA quantification with iPET evaluation may improve the early identification of patients at high risk of failing standard salvage therapy, who may benefit from an early switch to immunotherapeutic agents. Collectively, our results support the implementation of non‐invasive methods to detect minimal residual disease in recurrent cHL and justify its prospective evaluation in appropriately designed clinical trials. [ABSTRACT FROM AUTHOR]

Lymphatic vessels play a crucial role in activating anti-tumor immune surveillance but also contribute to metastasis and systemic tumor progression. Whether distinct lymphatic phenotypes exist that govern the switch between immunity and metastasis remains unclear. Here we reveal that cytotoxic immunity normalizes lymphatic function and uncouples immune and metastatic potential. We find that in mice and humans, intratumoral lymphatic vessel density negatively correlates with productive cytotoxic immune responses and identify IFNγ as an intrinsic inhibitor of lymphangiogenesis. Specific deletion of the Ifngr1 in lymphatic endothelial cells (LECs) greatly expanded the intratumoral lymphatic network and drove the emergence of a tip-like endothelial state, promoting lymph node metastasis but not dendritic cell migration. IFNγ inhibits oxidative phosphorylation, which is required for proliferation and acquisition of the pathologic transcriptional state. Our data indicate that IFNγ induces a phenotypic switch in tumor-associated lymphatic vessels to reinforce canonical immune surveillance and block metastasis., Competing Interests: Declaration of interests A.W.L. reports consulting services for AGS Therapeutics. All other authors declare no conflicts of interest.

Resident memory T cells (T RM ) provide rapid, localized protection in peripheral tissues to pathogens and cancer. While T RM are also found in lymph nodes (LN), how they develop during primary infection and their functional significance remains largely unknown. Here, we track the anatomical distribution of anti-viral CD8 + T cells as they simultaneously seed skin and LN T RM using a model of skin infection with restricted antigen distribution. We find exquisite localization of LN T RM to the draining LN of infected skin. LN T RM formation depends on lymphatic transport and specifically egress of effector CD8 + T cells that appear poised for residence as early as 12 days post infection. Effector CD8 + T cell transit through skin is necessary and sufficient to populate LN T RM in draining LNs, a process reinforced by antigen encounter in skin. Importantly, we demonstrate that LN T RM are sufficient to provide protection against pathogenic rechallenge. These data support a model whereby a subset of tissue infiltrating CD8 + T cells egress during viral clearance, and establish regional protection in the draining lymphatic basin as a mechanism to prevent pathogen spread., Competing Interests: Conflict of Interest AWL reports consulting services for AGS Therapeutics.