Abstract
Despite remarkable recent progress in treating solid cancers, especially the success of immunomodulatory antibody therapies for numerous different cancer types, it remains the case that many patients fail to respond to treatment. It is therefore of immense importance to identify biomarkers predicting clinical responses to treatment and patient survival, which would not only assist in targeting treatments to patients most likely to benefit, but might also provide mechanistic insights into the reasons for success or failure of the therapy. Several peripheral blood or tumor tissue diagnostic and predictive biomarkers known to be informative for cancer patient survival may be applicable for this purpose. The use of peripheral blood (“liquid biopsy”) offers numerous advantages not only for predicting treatment responses at baseline but also for monitoring patients on-therapy. Assessment of the tumor microenvironment and infiltrating immune cells also delivers important information on cancer-host interactions but the requirement for tumor tissues makes this more challenging, especially for monitoring sequential changes in the individual patient. In this contribution, we will review our findings on immune signatures potentially informative for clinical outcome in melanoma, breast cancer and renal cell carcinoma, particularly the outcome of checkpoint blockade, by applying multiparametric flow cytometry and mass cytometry, routine clinical monitoring and functional testing for predicting and following individual patient responses to therapy.
Highlights
The long-standing controversy as to whether the immune system performs immunosurveillance against cancer, as originally proposed by Burnet [1], and the accompanying skepticism as to whether immune-based treatments would ever be effective [2] was laid to rest with the development of clinically effective immunomodulatory antibody treatments [immune checkpoint inhibition, ICI [3]], culminating in the Nobel Prize for Physiology or Medicine in 2018
In an early study, using a 38-channel time-of-flight mass cytometry (CyTOF) approach in 2013 we investigated the peripheral immune landscape in what was at the time the largest cohort of stage IV melanoma patients and agematched healthy individuals subjected to this new technique [9]
Classical T cells, and T cells carrying the alternative γδ T cell receptor can exert strong anti-tumor, and under certain circumstances pro-tumor functions, as reviewed by others elsewhere [12]. We suggest that these cells must be considered when generating informative immune signatures because we found in a discovery study that low frequencies of Vδ1+ γδ T cells correlated with prolonged overall survival (OS) [13]
Summary
The long-standing controversy as to whether the immune system performs immunosurveillance against cancer, as originally proposed by Burnet [1], and the accompanying skepticism as to whether immune-based treatments would ever be effective [2] was laid to rest with the development of clinically effective immunomodulatory antibody treatments [immune checkpoint inhibition, ICI [3]], culminating in the Nobel Prize for Physiology or Medicine in 2018. For the purpose of monitoring response to therapy, and for ease of application in routine clinical settings, biomarkers established from a small sample of peripheral blood would offer many advantages over tissue biopsy. PERIPHERAL BIOMARKERS FOR MELANOMA ASSESSED AS IN VITRO T CELL RESPONSES TO TUMOR-ASSOCIATED ANTIGENS
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