Cutaneous Melanoma: Mutational Status and Potential Links to Tertiary Lymphoid Structure Formation

Abstract

Recent advances in immunotherapy have enabled rapid evolution of novel interventional approaches designed to reinvigorate and expand patient immune responses against cancer. An emerging approach in cancer immunology involves the conditional induction of tertiary lymphoid structures (TLS), which are non-encapsulated ectopic lymphoid structures forming at sites of chronic, pathologic inflammation. Cutaneous melanoma (CM), a highly-immunogenic form of solid cancer, continues to rise in both incidence and mortality rate, with recent reports supporting a positive correlation between the presence of TLS in melanoma and beneficial treatment outcomes amongst advanced-stage patients. In this context, TLS in CM are postulated to serve as dynamic centers for the initiation of robust anti-tumor responses within affected regions of active disease. Given their potential importance to patient outcome, significant effort has been recently devoted to gaining a better understanding of TLS neogenesis and the influence these lymphoid organs exert within the tumor microenvironment. Here, we briefly review TLS structure, function, and response to treatment in the setting of CM. To uncover potential tumor-intrinsic mechanisms that regulate TLS formation, we have taken the novel perspective of evaluating TLS induction in melanomas impacted by common driver mutations in BRAF, PTEN, NRAS, KIT, PRDM1, and MITF. Through analysis of The Cancer Genome Atlas (TCGA), we show expression of DNA repair proteins (DRPs) including BRCA1, PAXIP, ERCC1, ERCC2, ERCC3, MSH2, and PMS2 to be negatively correlated with expression of pro-TLS genes, suggesting DRP loss may favor TLS development in support of improved patient outcome and patient response to interventional immunotherapy.

Oncolytic adenovirus promotes vascular normalization and nonclassical tertiary lymphoid structure formation through STING-mediated DC activation

“…These features are also related to the reduced DNA repair ability and high mutational load of melanoma cells, which make it easier to transform the TME into a “hot tumor” and form an environment that induces TLS formation. 61 In addition, the existence of TLSs is closely related to immune checkpoint blockade (ICB). 38 Remark et al 62 found that TLSs were present in the tumors of patients undergoing neoadjuvant therapy (PD-1 inhibitor), which was associated with longer disease-free survival and overall survival.…”

Control of Dendritic Cell Function Within the Tumour Microenvironment

“…TLS are established at sites of chronic inflammation and can structurally and functionally resemble secondary lymphoid organs (120)(121)(122). Recent studies on murine models of TLS have shown the role of PDPN+ FAP+ immunofibroblasts in driving the development and expansion of TLSs (123,124).…”

STINGing the Tumor Microenvironment to Promote Therapeutic Tertiary Lymphoid Structure Development

“…This operating paradigm may underlie observations of cancers with reduced DNA repair proficiency and high comparative mutational burden presenting with brisk proinflammatory immune cell infiltrates (i.e. “hot tumors”) that are more prone to develop TLS ( 69 , 70 ) and to be more responsive to interventional immunotherapy ( 71 , 72 ). Notably, provision of low doses of STING agonists cGAMP and ADU-S100 (aka ML-RR-S2-CDA, MIW815) coordinately promote VN and CD8 + T cell-dependent control of tumor growth in murine models of breast carcinoma, lung carcinoma and melanoma ( 67 , 68 , 73 ).…”