Early disappearance of tumor antigen-reactive T cells from peripheral blood correlates with superior clinical outcomes in melanoma under anti-PD-1 therapy

Abstract

BackgroundAnti-programmed cell death protein 1 (PD-1) antibodies are now routinely administered for metastatic melanoma and for increasing numbers of other cancers, but still only a fraction of patients respond. Better understanding of the modes of action and predictive biomarkers for clinical outcome is urgently required. Cancer rejection is mostly T cell-mediated. We previously showed that the presence of NY-ESO-1-reactive and/or Melan-A-reactive T cells in the blood correlated with prolonged overall survival (OS) of patients with melanoma with a heterogeneous treatment background. Here, we investigated whether such reactive T cells can also be informative for clinical outcomes in metastatic melanoma under PD-1 immune-checkpoint blockade (ICB).MethodsPeripheral blood T cell stimulation by NY-ESO-1 and Melan-A overlapping peptide libraries was assessed before and during ICB in two independent cohorts of a total of 111 patients with stage IV melanoma. In certain cases, tumor-infiltrating lymphocytes could also be assessed for such responses. These were characterized using intracellular cytokine staining for interferon gamma (IFN-γ), tumor negrosis factor (TNF) and CD107a. Digital pathology analysis was performed to quantify NY-ESO-1 and Melan-A expression by tumors. Endpoints were OS and progression-free survival (PFS).ResultsThe initial presence in the circulation of NY-ESO-1- or Melan-A-reactive T cells which became no longer detectable during ICB correlated with validated, prolonged PFS (HR:0.1; p>0.0001) and OS (HR:0.2; p=0.021). An evaluation of melanoma tissue from selected cases suggested a correlation between tumor-resident NY-ESO-1- and Melan-A-reactive T cells and disease control, supporting the notion of a therapy-associated sequestration of cells from the periphery to the tumor predominantly in those patients benefitting from ICB.ConclusionsOur findings suggest a PD-1 blockade-dependent infiltration of melanoma-reactive T cells from the periphery into the tumor and imply that this seminally contributes to effective treatment.

Dynamics of Melanoma-Associated Epitope-Specific CD8+ T Cells in the Blood Correlate With Clinical Outcome Under PD-1 Blockade

“…Reasons for the disappearance of TAAspecific T cellsand thus also the loss of these mostly apparently clinically-beneficial MAE-specific CD8+ T cells -from the periphery might be diverse. This might be of particular relevance as we recently reported the early disappearance of functional Melan-Aor NY-ESO-1-reactive CD4+ and/or CD8+ T cells from the peripheral blood in some melanoma patients with superior OS and PFS under PD-1 ICB resulting from a hypothetical migration to the metastases (25). A similar pattern for the dynamics of NY-ESO-1-specific CD8+ T cells was also found in the present study.…”

“…Next, we aimed to identify the most relevant dynamics of certain MAE-specific CD8+ T cell populations through correlations with patients’ OS. We first noticed that similar to the previously studied NY-ESO-1 TAA ( 25 ), the disappearance of NY-ESO-1 QLS and SLL-specific T cells from the periphery tended to correlate with a prolonged OS under ICB (p=0.14; data not shown). Next, we performed several regression analyses in parallel and/or in sequence ( Figure 4A ) to identify those MAE-specific T cell populations with the greatest relevance for therapy outcome in an unbiased approach.…”

“…However, the (opposite) correlation of the loss of T cells specific for the TRP-2 SVY-, TAG-1 SLG- and Telomerase RLF-peptide-MHC complexes with OS noted here might be explained by these cells being dysfunctional or exhausted already before the start of ICB, as commonly reported in advanced stages of cancer ( 50 ). Taken together, we hypothesize that T cell specificity ( 37 ), kinetics of (ICB triggered) epitope accessibility ( 40 ) and essentially also functionality ( 20 – 22 , 24 , 25 ) at the single cell level might be considered as major features to classify T cell populations that actively contribute to cancer immunosurveillance as opposed to those from dysfunctional and/or anergic subsets that cannot be reinvigorated by ICB. Thus, such future evaluations of TAG-1-, Telomerase- and TRP-2-reactive T cells (including also CD4+ T cells) is warranted to discriminate between functionally competent and dysfunctional specific T cell clones, similar to our previous studies on MAGE-A3, Survivin-, Melan-A- and NY-ESO-1-reactive T cell populations ( 7 , 20 , 21 ).…”

“…Also, earlier studies by others revealed that these TAAs might be promising targets for active interventions ( 22 – 24 ). Recently, we reported that the dynamics of NY-ESO-1- and Melan-A-reactive T cells under PD-1 ICB are associated with clinical outcome ( 25 ). However, data on the impact of ICB on the presence of circulating TAA-specific T cells (beyond established epitopes like those from NY-ESO-1 or Melan-A) and conclusively the presence of their antigens in the tumors is still limited.…”

Robust diagnosis of infectious disease, autoimmunity and cancer from the paratope networks of adaptive immune receptors

“…Moreover, the close resemblance of the TCRs identified here to those found to be reactive to multiple types of cancer 31 further strengthens this argument. The notion that tumors can affect global migration from peripheral blood has been demonstrated in brain cancer and metastatic melanomas 39 . We thus believe that TCR-based classification of cancer from PBMCs will have applications not only for diagnosis but also for discovery of broadly protective anti-cancer T cells.…”