Diversity of the immune microenvironment and response to checkpoint inhibitor immunotherapy in mucosal melanoma
Joris L. Vos, Joleen J.H. Traets, Xiaohang Qiao, Iris M. Seignette, Dennis Peters, Michel W.J.M. Wouters, Erik Hooijberg, Annegien Broeks, Jacqueline E. van der Wal, M. Baris Karakullukcu, W. Martin C. Klop, Arash Navran, Marc van Beurden, Oscar R. Brouwer, Luc G.T. Morris, Mariette I.E. van Poelgeest, Ellen Kapiteijn, John B.A.G. Haanen, Christian U. Blank, Charlotte L. Zuur
Joris L. Vos, Joleen J.H. Traets, Xiaohang Qiao, Iris M. Seignette, Dennis Peters, Michel W.J.M. Wouters, Erik Hooijberg, Annegien Broeks, Jacqueline E. van der Wal, M. Baris Karakullukcu, W. Martin C. Klop, Arash Navran, Marc van Beurden, Oscar R. Brouwer, Luc G.T. Morris, Mariette I.E. van Poelgeest, Ellen Kapiteijn, John B.A.G. Haanen, Christian U. Blank, Charlotte L. Zuur
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Research Article Immunology Oncology

Diversity of the immune microenvironment and response to checkpoint inhibitor immunotherapy in mucosal melanoma

Abstract

Mucosal melanoma (MucM) is a rare cancer with a poor prognosis and low response rate to immune checkpoint inhibition (ICI) compared with cutaneous melanoma (CM). To explore the immune microenvironment and potential drivers of MucM’s relative resistance to ICI drugs, we characterized 101 MucM tumors (43 head and neck [H&N], 31 female urogenital, 13 male urogenital, 11 anorectal, and 3 other gastrointestinal) using bulk RNA-Seq and immunofluorescence. RNA-Seq data show that MucM has a significantly lower IFN-γ signature levels than CM. MucM tumors of the H&N region show a significantly greater abundance of CD8+ T cells, cytotoxic cells, and higher IFN-γ signature levels than MucM from lower body sites. In the subcohort of 35 patients with MucM treated with ICI, hierarchical clustering reveals clusters with a high and low degree of immune infiltration, with a differential ICI response rate. Immune-associated gene sets were enriched in responders. Signatures associated with cancer-associated fibroblasts, macrophages, and TGF-β signaling may be higher in immune-infiltrated, but ICI-unresponsive tumors, suggesting a role for these resistance mechanisms in MucM. Our data show organ region–specific differences in immune infiltration and IFN-γ signature levels in MucM, with H&N MucM displaying the most favorable immune profile. Our study might offer a starting point for developing more personalized treatment strategies for this disease.

Authors

Joris L. Vos, Joleen J.H. Traets, Xiaohang Qiao, Iris M. Seignette, Dennis Peters, Michel W.J.M. Wouters, Erik Hooijberg, Annegien Broeks, Jacqueline E. van der Wal, M. Baris Karakullukcu, W. Martin C. Klop, Arash Navran, Marc van Beurden, Oscar R. Brouwer, Luc G.T. Morris, Mariette I.E. van Poelgeest, Ellen Kapiteijn, John B.A.G. Haanen, Christian U. Blank, Charlotte L. Zuur

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Figure 2

Swimmer plot, progression-free survival, and overall survival of the subcohort of 35 patients with MucM treated with ICB.

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Swimmer plot, progression-free survival, and overall survival of the sub...
(A) Swimmer plot visualizing each patient treated with ICI as an individual bar. All bars begin at the point at which a patient first started ICI therapy and end at the last follow-up date; deaths from any cause are marked with an X. Bar colors indicate primary MucM location. Lines within bars indicate systemic palliative treatments, from the first to the last administered dose. Palliative radiotherapy and surgical interventions are marked with diamonds and triangles, respectively. CR, PR, and PD are marked with the symbols displayed in the legend. Patients with progressive disease in the context of a mixed response (MR) are indicated. The 2 patients with rapid symptomatic PD, in whom no imaging response assessment was performed, are included with the date of clinical progression as PD date. Please note that the x axis is interrupted twice. (B) Kaplan-Meier estimates and 95% CI for PFS since the start of the first ICI therapy for the whole ICI subcohort. (C) OS with 95% CI since the start of ICI therapy for the whole cohort. (D) PFS since the start of ICI, stratified per primary MucM region. P values were calculated using a 2-sided log-rank test. (E) OS since the start of ICI, stratified per primary MucM region. P values were calculated using a 2-sided log-rank test. (F) PFS since the start of ICI, stratified per best objective response. P values were calculated using a 2-sided log-rank test. (G) OS since the start of ICI, stratified per best objective response. The number at risk refers to the total number of patients who have not yet experienced the event of interest or been censored at the specified time points P values were calculated using a 2-sided log-rank test. RT, radiotherapy; PFS, progression-free survival; OS, overall survival; MucM, mucosal melanoma; H&N, head and neck; SN, sinonasal; OC, oral cavity, FUT, female urogenital tract; MUT, male urogenital tract; AR, anorectal; GI, gastrointestinal; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; MR, mixed response.