// Morten F. Gjerstorff 1 , Mads H. Andersen 2 and Henrik J. Ditzel 1,3 1 Department of Cancer and Inflammation Research, University of Southern Denmark, Odense, Denmark 2 Department of Haematology, Center for Cancer Immune Therapy (CCIT), Copenhagen University Hospital, Herlev, Denmark 3 Department of Oncology, Odense University Hospital, Odense, Denmark Correspondence to: Morten Gjerstorff, email: // Keywords : cancer/testis antigen, oncogenesis, immunotherapy Received : May 19, 2015 Accepted : June 21, 2015 Published : June 30, 2015 Abstract Recent developments have set the stage for immunotherapy as a supplement to conventional cancer treatment. Consequently, a significant effort is required to further improve efficacy and specificity, particularly the identification of optimal therapeutic targets for clinical testing. Cancer/testis antigens are immunogenic, highly cancer-specific, and frequently expressed in various types of cancer, which make them promising candidate targets for cancer immunotherapy, including cancer vaccination and adoptive T-cell transfer with chimeric T-cell receptors. Our current understanding of tumor immunology and immune escape suggests that targeting oncogenic antigens may be beneficial, meaning that identification of cancer/testis antigens with oncogenic properties is of high priority. Recent work from our lab and others provide evidence that many cancer/testis antigens, in fact, have oncogenic functions, including support of growth, survival and metastasis. This novel insight into the function of cancer/testis antigens has the potential to deliver more effective cancer vaccines. Moreover, immune targeting of oncogenic cancer/testis antigens in combination with conventional cytotoxic therapies or novel immunotherapies such as checkpoint blockade or adoptive transfer, represents a highly synergistic approach with the potential to improve patient survival.

/pdf/oncogenic-cancer-testis-antigens-prime-candidates-for-2eqcq0b49f.pdf

Oncogenic cancer/testis antigens: prime candidates for immunotherapy

Interleukins (IL)-1 and -6 have been shown to be produced by several categories of cells in the rat testis and involved in the paracrine control of testicular function. Evidence of high amounts of IL-1 have been shown in the human testis, but nothing is known about its cellular origin. Furthermore, to our knowledge, the presence of IL-6 in the human testis has not yet been investigated. Therefore, the present study was aimed at identifying IL-1 and -6 expression and production within the human testis, using RT-PCR, bioassays, and enzyme linked immunosorbent assays. We demonstrated that IL-1 and -6 messenger RNA and proteins were produced constitutively in vitro by human Leydig cell- and Sertoli cell-enriched preparations. FSH only stimulated IL-6 production by Sertoli cell-enriched preparations, but increased the release of both IL-1 and -6 in germ cell-depleted Sertoli cell cultures. In addition, lipopolysaccharides and latex beads enhanced the production of both cytokines by Sertoli cell cultures, whereas human chorionic gonadotropin and lipopolysaccharides enhanced the release of both cytokines by Leydig cells. Enzyme linked immunosorbent assays and neutralization experiments revealed that human Sertoli cells produce essentially the alpha form of IL-1, whereas both forms, alpha and beta, are present in Leydig cells. The demonstration that human Leydig and Sertoli cells produce IL-1 and -6 under the control of gonadotropin hormones and exogenous factors, opens the possibility to study the involvement of these cytokines in the control of testis function, in normal and pathological conditions in men.

Human Leydig cells and Sertoli cells are producers of interleukins-1 and -6.

Cancer testis antigens (CTAs) are of clinical interest as biomarkers and present valuable targets for immunotherapy. To comprehensively characterize the CTA landscape of non-small-cell lung cancer (NSCLC), we compared RNAseq data from 199 NSCLC tissues to the normal transcriptome of 142 samples from 32 different normal organs. Of 232 CTAs currently annotated in the Caner Testis Database (CTdatabase), 96 were confirmed in NSCLC. To obtain an unbiased CTA profile of NSCLC, we applied stringent criteria on our RNAseq data set and defined 90 genes as CTAs, of which 55 genes were not annotated in the CTdatabase, thus representing potential new CTAs. Cluster analysis revealed that CTA expression is histology dependent and concurrent expression is common. IHC confirmed tissue-specific protein expression of selected new CTAs (TKTL1, TGIF2LX, VCX, and CXORF67). Furthermore, methylation was identified as a regulatory mechanism of CTA expression based on independent data from The Cancer Genome Atlas. The proposed prognostic impact of CTAs in lung cancer was not confirmed, neither in our RNAseq cohort nor in an independent meta-analysis of 1,117 NSCLC cases. In summary, we defined a set of 90 reliable CTAs, including information on protein expression, methylation, and survival association. The detailed RNAseq catalog can guide biomarker studies and efforts to identify targets for immunotherapeutic strategies.

/pdf/profiling-cancer-testis-antigens-in-non-small-cell-lung-4n0y84p4zl.pdf

Profiling cancer testis antigens in non–small-cell lung cancer

From conception to old age, the major histocompatibility complex (MHC) is at the centre of immune responses that aid survival, fitness and adaptation of mammalian species to the environment. Its main function is that of controlling adaptive immunity, particularly T-cell-mediated immunity towards pathogens. In several species, including humans, the MHC is also able to elicit T-cell-mediated immune responses to allogeneic MHC antigens (non-self MHC antigens expressed by another individual from the same species). Although this phenomenon was originally identified in mice by the somewhat unnatural means of tissue transplantation, it was soon realized that it may also play an important role in the natural state, since the mammalian fetus in the maternal uterus is semi-allogeneic, due to the presence of MHC genes inherited from the father. Thus, during normal pregnancy the maternal immune system undergoes changes that lead to tolerance of the fetus. The MHC can play a dual role in the reproduction process: firstly influencing mating choice in some species, affecting the mother‐father MHC matching; and secondly influencing the development of the fertilized ovum during the preimplantation period. In this review we examine the role of the MHC at three distinct levels: (i) MHC expression in gametes and its role in fertilization; (ii) MHC expression in placental tissue; and (iii) MHC expression in embryonic tissue. We suggest that the MHC plays a pleiotropic role, both in fitness (survival and reproductive success) and in development, thereby ensuring the survival of the species in future generations.

/pdf/a-critical-review-of-the-role-of-the-major-4ow9l7nbqq.pdf

A critical review of the role of the major histocompatibility complex in fertilization, preimplantation development and feto-maternal interactions

HLA expression on immature and mature human germ cells

We have studied mRNA expression for Class I HLA (human leukocyte antigen) on male germ cells by amplification of gene fragments in PCR techique and by Northern hybridization. RNA was extracted from fractionated gametogenic cells (isolated from testis) and reversely transcribed. Then, cDNA was amplified for specific HLA sequence (1151 bp) representing whole-length coding sequence (HLA, -A, -B, -C). The specificity of this product was confirmed in “nested” PCR of 400 bp gene fragment coding for alpha 2 domain, alpha 3 domain, and the transmembrane portion of Class I HLA. The results indicate minimal expression of classical Class I HLA on gametogenic cells. Northern hybridization with 669 bp cDNA fragment (spanning for alpha 3 domain, transmembrane, cytoplasmic, and 3′ untraslated region) resulted in a low intensity signal from gametogenic cell fractions and confirmed our findings obtained by PCR. The minimal expression of classical HLA antigens may create a neutral cover for the male reproductive system, thereby preventing an immunological response during germ cell differentiation. © 1994 Wiley-Liss, Inc.

Analysis of mRNA for class I HLA on human gametogenic cells

Analysis of mRNA expression for interleukin-1 genes on human testicular cells

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Analysis of mRNA for class I HLA on human gametogenic cells

Analysis of mRNA expression for interleukin-1 genes on human testicular cells