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Review
. 2021 Mar 4:12:629519.
doi: 10.3389/fimmu.2021.629519. eCollection 2021.

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

Deepak Salem  1 , Manoj Chelvanambi  2 , Walter J Storkus  2   3   4   5 , Ronald J Fecek  1
Affiliations
Review

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

Deepak Salem et al. Front Immunol. .

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.

Keywords: DNA repair proteins; cutaneous melanoma; driver mutations; tertiary lymphoid structures; tumor mutational burden.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Correlation of DNA repair proteins with pro-TLS genes. TCGA data from two cohorts of cutaneous melanoma patients (SKCM_DFCI 2015 and SKCM_MSKCC 2014) was included to analyze if expression of DNA repair proteins correlated with the expression of inflammatory markers within the TME. TCGA data was uploaded onto cBio Portal, a published TCGA data analysis tool (86, 87), and correlative mRNA expression of the above inflammatory and DNA repair proteins visualized using linear regression models. Pearson's coefficients from each correlation is visualized as a heatmap (created using the Prism 8 software) above with positive correlations indicated in red and negative correlations indicated in green.
Figure 2
Figure 2
Proposed intrinsic molecular mechanisms that contribute to TLS development downstream of common driver mutations in cutaneous melanoma. Pro-inflammatory cues initiate TLS neogenesis in the peripheral tumor microenvironment (TME). In a melanoma tumor cell, loss of tumor suppressor genes PTEN and PRDM1 results in increased expression of STAT3 and SOX-10, respectively. Gain of function in the proto-oncogenes BRAF, KIT, MITF results in upregulation of MEK, ERK, and HIF-1α, respectively. Culmination of these mutations results in increased expression of pro-TLS cytokines (CCL21, CCL19, CXCL13, LTa1b2) and pro-inflammatory immune cell recruitment (T cell, B cell) contributing to the development, maintenance, and function of TLS in the TME (Inflammatory phenotype). The lack of proinflammatory cues in the TME contributes to the recruitment and maintenance of immunoregulation (Treg, MDSC) resulting in an immunosuppressive TME (Immunosuppressive phenotype). The ever-changing balance of pro-inflammatory vs. regulatory immune function in TLS likely dictates the anti- vs. pro-tumor influence TLS play in disease outcome. LTi cell, Lymphoid tissue inducer cell; MDSC, Myeloid derived suppressor cell; DC, Dendritic cell; NK cell, Natural killer cell. Created with BioRender.com.
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