Circulating immune landscape in melanoma patients undergoing anti-PD1 therapy reveals key immune features according to clinical response to treatment

Introduction: Immune checkpoint blockers (ICB) bring unprecedented clinical success, yet many patients endure immune mediated adverse effects and/or fail to respond. Predictive signatures of response to ICB and mechanisms of clinical efficacy or failure remain understudied. DC subsets, in network with conventional αβ T (T_conv), NK, γδ T and iNKT cells, harbor pivotal roles in tumor control, yet their involvement in response to ICB remained underexplored.

Methods: We performed an extensive longitudinal monitoring of circulating immune cells from melanoma patients treated with first-line anti-PD1, before (T0) and during treatment. We assessed the phenotypic and functional features of DC and effector cells' subsets by multi-parametric flow cytometry and ProcartaPlex^® dosages.

Results: We revealed differences according to response to treatment and modulations of patterns during treatment, highlighting a strong link between the immune landscape and the outcome of anti-PD1 therapy. Responders exhibited higher frequencies of circulating cDC1s, CD8⁺ T cells, and γδ2⁺ T cells in central memory (CM) stage. Notably, we observed a distinct remodeling of ICP expression profile, activation status and natural cytotoxicity receptor patterns of immune subsets during treatment. Anti-PD1 modulated DCs' functionality and triggered deep changes in the functional orientation of T_conv and γδT cells.

Discussion: Overall, our work provides new insights into the immunological landscape sustaining favorable clinical responses or resistance to first-line anti-PD1 therapy in melanoma patients. Such exploration participates in uncovering the mechanism of action of anti-PD1, discovering innovative predictive signatures of response, and paves the way to design pertinent combination strategies to improve patient clinical benefits in the future.