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The addition of stereotactic ablative radiotherapy (SABR) to immune checkpoint inhibitors (ICIs) has the potential to significantly improve outcomes in the treatment of metastatic melanoma. We analysed peripheral blood immune cells of patients receiving combination SABR and ICI to detect the effect of treatment and identify potential biomarkers that predict outcome.24 polymetastatic melanoma patients participated in the SABR IMPACT trial, receiving standard dose immunotherapy with anti-PD-1 and/or anti-CTLA-4 and stereotactic ablative radiotherapy to one site. Comprehensive immunophenotyping of T-cells was performed with flow cytometry on blood samples from 13 patients at baseline and following the first 4 cycles of treatment.Following four cycles of immunotherapy and SABR, the proportion of naïve subsets were reduced within both the CD4 and CD8 T-cell lineages. Independently, SABR resulted in increased expression of PD-1 (p = 0.019) and ICOS (p = 0.046) on the CD8+ T-cells, accompanied by a reduction in regulatory T-cell frequencies (p = 0.048). A multivariate discriminant analysis revealed a baseline signature of lower levels of CD8+ naive T-cells and higher expression of TIM-3 on regulatory T-cells and memory T-cells better predicted response.The combination of immunotherapy and SABR changed the immunophenotype of blood T cells, with some shifts attributable to SABR. Importantly, we identified a T-cell signature at baseline that best predicted response. Validation of these findings in an independent cohort could confirm these as biomarkers at baseline or early during treatment, and whether these can be utilised to stratify patients for high or low intensity treatment to reduce toxicity.

Functionally diverse T cell populations interact to maintain homeostasis of the immune system. We found that human and mouse antigen-activated T cells with high expression of the lymphocyte surface marker CD52 suppressed other T cells. CD52(hi)CD4(+) T cells were distinct from CD4(+)CD25(+)Foxp3(+) regulatory T cells. Their suppression was mediated by soluble CD52 released by phospholipase C. Soluble CD52 bound to the inhibitory receptor Siglec-10 and impaired phosphorylation of the T cell receptor-associated kinases Lck and Zap70 and T cell activation. Humans with type 1 diabetes had a lower frequency and diminished function of CD52(hi)CD4(+) T cells responsive to the autoantigen GAD65. In diabetes-prone mice of the nonobese diabetic (NOD) strain, transfer of lymphocyte populations depleted of CD52(hi) cells resulted in a substantially accelerated onset of diabetes. Our studies identify a ligand-receptor mechanism of T cell regulation that may protect humans and mice from autoimmune disease.