HLA-I loss in germ cell tumors of the testis: potential implications for immune evasion, preservation of the stem cell phenotype, and reprogramming.

INTRODUCTION: Previous studies have analyzed the "reprogramming" of germ cell tumors of the testis (GCTT), which is a complex genetic/epigenetic process regulated by tumor microenvironment (TME) and resulting in the preservation of stem cell features and/or the differentiation of GCTT. Human leukocyte antigens class I (HLA-I) is a key regulator of the interactions between tumor cells and TME, but few studies have studied its expression in GCTT, germ cell neoplasia in situ (GCNIS), and "normal" adjacent testis (AT). METHODS: We tested 102, 41 and 26 GCTT components, GCNIS, and AT, respectively. HLA-I expression was scored (intact/retained, sub-clonal loss, and complete loss), dichotomized, and compared between different subgroups by adopting Fisher's exact test. RESULTS: We found that HLA-I loss was more frequent in seminoma (S) and embryonal carcinoma (EC) rather than in the other non-seminomatous GCTT (NS-GCTT) (p<0.001 and p: 0.002). HLA-I was positive in all GCNIS (41/41, 100%), thus being statistically significant compared to both GCTT (p<0.001) and AT (p<0.001). HLA-I loss was found in all AT (26/26, 100%), with a characteristic "patterned" expression (loss in spermatids, spermatozoa, and spermatogonia; expressed by spermatocytes). CONCLUSIONS: "HLA-I loss" varies during the GCTT reprogramming, thus supporting its role in the crosstalk between TME and GCTT, which is crucial for the maintenance of stem cell features (S and EC) and specific differentiation programs (other NS-GCTT). Future studies are needed to explore its role in GCNIS and AT.