Emerging roles of the MAGE protein family in stress response pathways

The melanoma antigen (MAGE) proteins all contain a MAGE homology domain. MAGE genes are conserved in all eukaryotes and have expanded from a single gene in lower eukaryotes to ∼40 genes in humans and mice. Whereas some MAGEs are ubiquitously expressed in tissues, others are expressed in only germ cells with aberrant reactivation in multiple cancers. Much of the initial research on MAGEs focused on exploiting their antigenicity and restricted expression pattern to target them with cancer immunotherapy. Beyond their potential clinical application and role in tumorigenesis, recent studies have shown that MAGE proteins regulate diverse cellular and developmental pathways, implicating them in many diseases besides cancer, including lung, renal, and neurodevelopmental disorders. At the molecular level, many MAGEs bind to E3 RING ubiquitin ligases and, thus, regulate their substrate specificity, ligase activity, and subcellular localization. On a broader scale, the MAGE genes likely expanded in eutherian mammals to protect the germline from environmental stress and aid in stress adaptation, and this stress tolerance may explain why many cancers aberrantly express MAGEs. Here, we present an updated, comprehensive review on the MAGE family that highlights general characteristics, emphasizes recent comparative studies in mice, and describes the diverse functions exerted by individual MAGEs.

Detecting Melanoma Antigen Family A3 Expression in Solid/Non-Solid Human Tumor

Background: MAGEA3 is a member of melanoma antigen family and has been recognized to express in many types of human cancers recently. In spite of the development of cancer vaccine, the prognostic value of MAGEA3 has not been well evaluated, due to the variability of clinical data and lack of clinical trials on the prognostic values.Method: Studies that evaluated MAGEA3 expression with a follow-up for at least 36 months were selected by searching in PubMed, WOS, Cochrane library, Embase. Published data was recorded and calculated into odds ratios (OR) for mortality in three or five years with Mantel-Haenszel random-effect model. Results: 11 studies were selected. The median positive rate was 45%. MAGEA3 always combines with worse survival on three or five years survival. The correlation between MAGEA3 and squamous carcinoma seemed stronger than adenocarcinoma on three-year OS while things got a reverse when it came to five-year OS. Most importantly, we found that all solid tumors originated from endoderm seemed to enjoy a strongest correlation among all the three germ layers.Conclusion: In this meta-analysis, we found that the expression of MAGEA3 can connect with worse outcome, and it probably can be a predictor for patients’ prognosis in clinical practice.

Nested tandem duplications of the gene Melanoma antigen recognized by T-cells (Mlana) underlie the sexual dimorphism locus in domestic pigeons

Birds have classic examples of exaggerated sexually dimorphic traits, including colors. Sexes among the wild rock dove and its derived domestic breeds, however, are quite indistinguishable and sex can only be ascertained through genotyping or egg laying and successful hatching of eggs. Yet, the pigeon fancy has discovered sexually dimorphic traits and harnessed some of these traits in some auto-sexing breeds. Early genetics pioneers characterized the sex-linked Stipper locus and showed it to be linked to the pigeon Z linked B-locus (Tyrp1). The alleles of the Stipper locus have variable dominance relative to wild-type (more severe alleles are incompletely dominant, less severe alleles are reportedly fully dominant), characterized by a continuum of lightening in homozygotes and increased variegation in heterozygotes corresponding with severity. We leveraged this positional information and population structure among breeds in a candidate gene approach to identify the genetic mechanism of de novo pigeon sex dichromatism. A large tandem duplication (77 kb) centered on the gene Melanoma antigen recognized by T cells (Mlana) is completely associated with alleles of the Stipper locus. Copy number of the 77 kb genetic lesion was not correlated with allele severity suggesting that other mechanisms, including epigenetic regulation could underlie both allele severity and degree of variegation.

Resensitization of uveal melanoma (UM) to immune checkpoint inhibition (ICI) by IMCgp100 (IMC).

9592 Background: ICI responses in UM are rare (~5% with anti-CTLA4/PD1 monotherapy; 10-12% with combination ICI). IMC is a bispecific agent composed of a high affinity T cell receptor targeting the gp100 melanoma antigen fused to an anti-CD3 scFv that increases intratumoral CD8+ T cell infiltration and PD1/PDL1 expression, and may enhance response to post-IMCgp100 ICI. Methods: We previously reported on 19 UM pts treated in the phase I dose escalation cohort of IMC (IMCgp100-102). We performed a retrospective analysis of clinical features and response to pre- and post-IMC ICI for the 12 pts in this cohort as well as 17 other pts (n = 29) treated with post-IMC ICI at 7 centers from 8/2016 to 1/2019. 21/29 pts (including 10/12 pts from IMCgp100-102) are evaluable for response and/or survival and are included in the analysis. Results: Baseline characteristics (n = 21): median age 56 (range 45-69); 57% female; median number of prior therapies 2 (range 1-4). Pre- and post-IMC ICI included: IPI+NIVO (3 pre; 8 post), anti-PD1 monotherapy (7 pre; 8 post), and anti-CTLA4 monotherapy (4 pre; 5 post). 20 pts were evaluable for post-IMC ICI response (1 died before restaging): 3/20 (15%) had partial responses (53-78% regression); 5/20 (25%) had stable disease (SD) > 16 weeks; 1/20 had SD of unknown duration. Median PFS and OS from the initiation of post-IMC ICI were 4.9 (95% CI 2.7-10.7) and 10.1 (95% CI 5.7-NR) months, respectively. 13 pts received pre-IMC ICI, all with eventual disease progression. 3 pts had treatment duration or SD lasting > 6 months. Of these 3 pts, 2 had clinical benefit (defined as objective response or SD > 16 weeks) with post-IMC ICI. There was no clear association between rates of Gr ≥ 2 irAE with pre- or post-IMC ICI and response. For the 10 evaluable pts treated on IMCgp100-102, no marked difference in prior response to IMC (3 SD among 5 ICI responders vs 2 SD among 4 ICI non-responders) or mean tumor shrinkage with IMC (-14.0% vs -18.0%) was observed, but rates of Gr ≥ 2 fever, rash, and/or hypotension with IMC were higher among ICI responders (80% vs 50%). Conclusions: Survival outcomes with post-IMC ICI compare favorably to historical figures in pretreated UM pts. IMC may re-sensitize pts who had prior clinical benefit with ICI to subsequent ICI.