CD4+ T cells orchestrate the immune response to ALK-positive T-cell lymphoma.

Immunotherapy has revolutionized the treatment of solid cancers in recent years. However, T-cell lymphomas (T-NHLs) originate from immune cells themselves and are biologically heterogeneous, rendering investigations of immune checkpoint inhibitor (ICI) mechanisms of action complex. While case reports and individual Anaplastic Large Cell Lymphoma (ALCL) cases enrolled in T-NHL trials demonstrated favourable responses to ICI, hyperprogression was observed in other T-NHL subtypes. We therefore utilized a syngeneic mouse model of ALK+ ALCL to investigate immune surveillance and ICI-induced immune response. Transplantation experiments combined with depletion of relevant immune axes revealed that ALCL immune surveillance is mediated by CD4+ T cells and NK cells. Innate and adaptive immune cell infiltration was confirmed on a large series of primary human ALK+ ALCL samples. ICI monotherapy demonstrated robust efficacy in murine ALCL, inducing complete remissions in approximately 50% of treated animals. Mechanistically, PD-L1 blockade reversed Treg-mediated immunosuppression and increased the frequency of circulating effector CD8+ T lymphocytes, thereby prolonging survival significantly. Importantly, CD4+ T cells proved indispensable for driving and sustaining immunotherapy-induced anti-tumour responses in murine ALCL. CD4+ T cells of non-responder animals exhibited an exhausted phenotype and a transcriptomic Th22-like signature, implicating persistent T-cell exhaustion and polarization as a meaningful immune-evasion mechanism. Our findings uncover CD4+ T cells as key players in spontaneous and immunotherapy-mediated anti T-cell lymphoma immunity, which demonstrates the critically needed preclinical proof-of-concept for the safe and effective use of immunotherapy for ALCL.