Innate immune checkpoint inhibitor resistance is associated with melanoma sub-types exhibiting invasive and de-differentiated gene expression signatures

Abstract

Melanoma is a highly aggressive skin cancer, which, although highly immunogenic, frequently escapes the body’s immune defences. Immune checkpoint inhibitors (ICI), such as anti-PD1, anti-PDL1, and anti-CTLA4 antibodies lead to reactivation of immune pathways, promoting rejection of melanoma. However, the benefits of ICI therapy remain limited to a relatively small proportion of patients who do not exhibit ICI resistance. Moreover, the precise mechanisms underlying innate and acquired ICI resistance remain unclear. Here, we have investigated differences in melanoma tissues in responder and non-responder patients to anti-PD1 therapy in terms of tumour and immune cell gene-associated signatures. We performed multi-omics investigations on melanoma tumour tissues, which were collected from patients before starting treatment with anti-PD1 immune checkpoint inhibitors. Patients were subsequently categorized into responders and non-responders to anti-PD1 therapy based on RECIST criteria. Multi-omics analyses included RNA-Seq and NanoString analysis. From RNA-Seq data we carried out HLA phenotyping as well as gene enrichment analysis, pathway enrichment analysis and immune cell deconvolution studies. Consistent with previous studies, our data showed that responders to anti-PD1 therapy had higher immune scores (median immune score for responders = 0.1335, median immune score for non-responders = 0.05426, p-value = 0.01, Mann-Whitney U two-tailed exact test) compared to the non-responders. Responder melanomas were more highly enriched with a combination of CD8+ T cells, dendritic cells (p-value = 0.03) and an M1 subtype of macrophages (p-value = 0.001). In addition, melanomas from responder patients exhibited a more differentiated gene expression pattern, with high proliferative- and low invasive-associated gene expression signatures, whereas tumours from non-responders exhibited high invasive- and frequently neural crest-like cell type gene expression signatures. Our findings suggest that non-responder melanomas to anti-PD1 therapy exhibit a de-differentiated gene expression signature, associated with poorer immune cell infiltration, which establishes a gene expression pattern characteristic of innate resistance to anti-PD1 therapy. Improved understanding of tumour-intrinsic gene expression patterns associated with response to anti-PD1 therapy will help to identify predictive biomarkers of ICI response and may help to identify new targets for anticancer treatment, especially with a capacity to function as adjuvants to improve ICI outcomes.

Dynamical modelling of proliferative-invasive plasticity and IFNγ signaling in melanoma reveals mechanisms of PD-L1 expression heterogeneity

“…These cells also have reduced IFNγ signaling activity (Fig 5D). This trajectory was recently reported in experimental data demonstrating that melanoma patients responding to anti-PD-1 therapy exhibit a more proliferative gene expression signature, while the non-responders were enriched in invasive and neural crest-like phenotypes (59). Moreover, vemurafenib-resistant clones of A375 and 451Lu cells display similar molecular attributes (Fig 5E).…”

Phenotype Switching and the Melanoma Microenvironment; Impact on Immunotherapy and Drug Resistance

“…Although immune checkpoint inhibitor-based therapies are somewhat more promising than targeted therapies in achieving complete cures, for most patients, intrinsic or acquired resistance remains a key obstacle. Hossain et al (2022) [ 50 ] showed that non-responding melanomas to anti-PD1 therapy are enriched for genes characteristic of undifferentiated and neural crest-like differentiation states, while in contrast, responding melanomas to anti-PD1 therapy exhibit expression signatures mainly characterized by transitory and melanocytic state gene signatures, supporting the notion that phenotype switching behavior characterizes responding versus non-responding melanomas ( Figure 1 ). The same study also showed an association between phenotype switching, immune cell composition in the TME, and the presence of innate resistance to anti-PD1 therapy.…”

Tunable PhenoCycler Imaging of the Murine Pre-Clinical Tumour Microenvironments

“…To this end, ICI therapies have revolutionized the treatment of melanoma, but innate and acquired resistance remain as clinical challenges. Furthermore, clinical studies have shown that ICI resistance is associated with changes in TME composition (61, 62).…”