Abstract
Immune checkpoint inhibition has resulted in dramatic improvements in overall and relapse-free survival in patients with metastatic melanoma. The most commonly used immune checkpoint inhibitors are monoclonal antibodies targeting programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4. Unfortunately, a significant subset of patients fail to respond to these therapies, which has resulted in intense research efforts to identify the factors which are associated with treatment response. To this end, we investigated immune cell infiltration in primary melanomas and melanoma metastases, in addition to tumor cell PD-L1 expression, to determine whether these factors are associated with an improved outcome after immune checkpoint inhibition. Indeed, the extent of the immune cell infiltration in the primary melanoma, measured by the Immunoscore, was associated with a significantly improved response to immune checkpoint inhibition in terms of increased overall survival. However, the Immunoscore did not predict which patients would respond to treatment. The Immunoscore was significantly reduced in metastases when compared to primary melanomas. In contrast, PD-L1 expression, exhaustively tested using four commercially available anti-PD-L1 clones, did not differ significantly between primary tumors and melanoma metastases and was not associated treatment response. Whilst replication in larger, prospective studies is required, our data demonstrates the relevance of immune cell infiltration in the primary melanoma as a novel marker of improved overall survival in response to immune checkpoint inhibition.
Highlights
Melanoma is highly refractory to treatment with conventional chemotherapy, the advent of immune checkpoint inhibition has dramatically improved the clinical outcome in metastatic disease [1]
2 Patients were treated with Ipilimumab monotherapy. 12 patients were treated with Nivolumab (n = 6) or Pembrolizumab (n = 6). 11 patients received Ipilimumab prior to anti-PD-1-therapy, 4 patients received Ipilimumab prior to combined therapy with Ipilimumab and a PD-1-inhibitor and 3 patients initially received combination therapy with Ipilimumab and a PD1-inhibitor followed by a PD-1-inhibitor (Table 1)
We assessed the Immunoscore in a total of 22 samples of primary melanomas; 13 (59.1%) were classified as brisk and 9 (40.9%) samples were classified as nonbrisk
Summary
Melanoma is highly refractory to treatment with conventional chemotherapy, the advent of immune checkpoint inhibition has dramatically improved the clinical outcome in metastatic disease [1]. Whilst immune checkpoint inhibition has been associated with impressive long-term response rates, there remains a subset of patients who either fail to respond to therapy (primary resistance), or lose the initial response (secondary resistance) during treatment [2]. An increased tumor mutational load is associated with improved outcome under checkpoint inhibition, potentially via the induction of immune cells which differentially recognize tumor- from normal cells [4, 5]. Melanoma can express a specific mutational profile which is able to induce an innate antiPD1 resistance (IPRES) phenotype, rendering the melanoma effectively unresponsive to immune checkpoint inhibition [6]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
