In Regard to Smart et al

I first wish to congratulate Smart and colleagues for providing an excellent report that adds to the dearth of literature focused on mucosal melanoma.1Smart AC, Giobbie-Hurder A, Desai V, et al. Multicenter evaluation of radiation and immune checkpoint inhibitor therapy in mucosal melanoma and review of recent literature. Adv Radiat Oncol. 2023;101310. Accessed July 21, 2023. https://doi.org/10.1016/j.adro.2023.101310.Google Scholar Combination therapy, especially with immunotherapy, is undoubtedly a central topic at the frontier of our expanding novel radiotherapeutic armamentarium. This is especially true in disease such as mucosal melanoma that does not display good clinical response to immune checkpoint inhibitors (ICIs). Tantalizing fundamental biologic questions also emerge from such work. In the report by Smart and colleagues, 37 patients received immunotherapy, either cytotoxic T-lymphocyte-associated protein 4 (CTLA4) (8%), programmed cell death protein 1 (PD-1/PD-L1) (51%), or a combination of both (41%). Immunotherapy was provided before radiation therapy (RT) for 5 patients (14%), concomitantly with RT for 9 patients (24%), after RT for 5 patients (14%), and at recurrence or metastasis in 18 patients (49%).1Smart AC, Giobbie-Hurder A, Desai V, et al. Multicenter evaluation of radiation and immune checkpoint inhibitor therapy in mucosal melanoma and review of recent literature. Adv Radiat Oncol. 2023;101310. Accessed July 21, 2023. https://doi.org/10.1016/j.adro.2023.101310.Google Scholar There was frank heterogeneity in the timing of immunotherapy use, which is coherent with reports from other groups. The authors have done a great job of trying to unveil associations between outcomes and treatment variables. However, although implicitly of limited validity, further dissecting the timing of ICI use with RT could be of interest, especially in melanoma. The work of Karras and colleagues has shown that distinct cellular populations display specific cell fate in melanoma.2Karras P. Bordeu I Pozniak J et al.A cellular hierarchy in melanoma uncouples growth and metastasis.Nature. 2022; 610: 190-198Crossref PubMed Scopus (40) Google Scholar Cells poised to grow rapidly do not possess the intrinsic phenotypic competency of metastatic dissemination, an ability that appears circumscribed to another subpopulation. These authors also suggest that these capabilities can be dynamically altered, contingent upon the immune microenvironment within which cells are embedded. It would be interesting to determine whether ICI timing (pre-, post- or intratreatment) could modify local control or alter tumoral ability to disseminate systemically through selective inhibitory pressure on a subpopulation of melanoma cells. Alternatively, perhaps the immunomodulatory effects of ICI could, depending on their timing with RT, promulgate this dynamic regulation of a melanoma subcellular population's phenotypical switch. This could alter systemic response to RT (abscopal) in these lesions. For example, concomitant PD-1 blockade has been suggested to potentiate the abscopal effect, specifically in melanoma,3Trommer M Yeo SY Persigehl T et al.Abscopal effects in radio-immunotherapy-response analysis of metastatic cancer patients with progressive disease under anti-PD-1 immune checkpoint inhibition.Front Pharmacol. 2019; 10: 511Crossref PubMed Scopus (49) Google Scholar and RT could potentiate ipilimumab in patients with non-small cell lung cancer, possibly in an abscopal-dependent way.4Formenti SC Rudqvist NP Golden E et al.Radiotherapy induces responses of lung cancer to CTLA-4 blockade.Nat Med. 2018; 24: 1845-1851Crossref PubMed Scopus (565) Google Scholar Contrarily, phenotypical switching to mesenchymal-like cells with heightened metastatic potential and reduced proliferative capabilities could hinder RT response,5Wang KX Cui WW Yang X et al.Mesenchymal stem cells for mitigating radiotherapy side effects.Cells. 2021; 10: 294Crossref PubMed Scopus (18) Google Scholar which could drive differences in local as well as distant recurrences. More work is needed to uncover the nuanced and intricate interplay between microenvironment, ICIs, melanoma cells, and radiotherapeutic effects. Such improved understanding could benefit patients by improving local control or preventing systemic recurrence. The author declares no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. In Reply to FabiAdvances in Radiation OncologyVol. 9Issue 1PreviewWe appreciate Fabi's thoughtful commentary on our study regarding the importance of future work to address the optimal timing of immune checkpoint inhibitors (ICIs) relative to radiation therapy (RT) for mucosal melanoma.1 There is biologic rationale to suggest that both local control and systemic response may be affected by synergistic actions of RT and ICIs, although this remains to be proven in clinical practice.2 Full-Text PDF Open Access

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