Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma

Abstract

Ipilimumab has revolutionized malignant melanoma therapy, but a better understanding of the mechanisms behind treatment response and adverse effects is needed. In this work, the immune system of ipilimumab treated patients was monitored to investigate potential mechanisms of action that may correlate with treatment outcome. Blood samples from 43 advanced melanoma patients were taken before, during and at the end of treatment. Hematological parameters were measured and flow cytometry analysis was performed in fresh samples within two hours of sample collection. Strong differences in markers CD45RA, CCR7, HLA-DR and CD15 between fresh and cryopreserved samples were observed. Ipilimumab treatment increased absolute lymphocyte counts, eosinophils, effector T cells and their activation status, whilst diminishing the suppressive side of the immune response, acting on regulatory T cells and myeloid derived suppressor cells (MDSCs). These effects were visible after one ipilimumab infusion and, regarding eosinophil counts, correlated with onset of adverse events. Monocytic MDSCs were decreased in response to treatment only in patients with clinical benefit; additionally, patients with a lower frequency of these cells after the first ipilimumab infusion experienced increased overall survival. CD8 effector memory T cell frequencies at the end of treatment were higher in patients with clinical benefit and positively correlated with survival. These data show that a clinical response to ipilimumab not only requires reshaping T cell populations, but additionally involves a reduction in suppressive cells such as monocytic MDSCs. Our work could provide insight on predicting treatment outcome, assisting clinicians in offering the best personalized therapeutic approach.

NK‐ and T‐cell subsets in malignant mesothelioma patients: Baseline pattern and changes in the context of anti‐CTLA‐4 therapy

“…This will hopefully help to "reprogram" immune cells to promote a more effective response. Based on other and our own studies in patients with melanoma, 29,32 we chose to not only analyze T-cell subsets but specifically focus on NK cells. It should be noted that NK cells may participate in immune checkpoint therapy in several ways, including as effector cells (ADCC, natural cytotoxicity and cytokine production) that can be stimulated by T-cell cytokines, where they could be particularly important in the elimination of cancer cells that fail to present antigens that are recognized by CD8 + T cells.…”

Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way

“…Ipilimumab binds to CTLA-4 expressed on T cells and inhibits the CTLA-4-mediated downregulation of T-cell activation, leading to a cytotoxic T-cell-mediated immune response against cancer cells. The detailed mechanisms of action of CTLA-4 blockade with ipilimumab are not fully understood, but it is estimated that they can be classified into two main types: cell-intrinsic mechanisms acting in cis and cell-extrinsic mechanisms acting in trans (de Coana et al 2017). The cis mechanisms involve Figure 1 Immunological synapse, showing tight contact between a T cell and an antigen-presenting cell.…”

T‐cell cross‐reactivity may explain the large variation in how cancer patients respond to checkpoint inhibitors

“…For ipilimumab therapy, improved response was found to be associated with rapid alteration of MDSC subsets after treatment. 69,71 The patients who benefited most appeared to be those with decreased monocytic MDSC counts at week 3 after the first injection of ipilimumab. 71 Similarly, reduction in Treg population and increase in absolute lymphocyte counts have been associated with clinical benefit to ipilimumab treatment.…”

“…69,71 The patients who benefited most appeared to be those with decreased monocytic MDSC counts at week 3 after the first injection of ipilimumab. 71 Similarly, reduction in Treg population and increase in absolute lymphocyte counts have been associated with clinical benefit to ipilimumab treatment. 72 Although further work is needed, early alteration in blood MDSCs and Treg counts during treatment is important and should benefit patients by providing reliable guidelines for therapy monitoring.…”