Mechanisms of immune modulation in the tumor microenvironment and implications for targeted therapy.

The efficacy of cancer therapies is limited to a great extent by immunosuppressive mechanisms within the tumor microenvironment (TME). Numerous immune escape mechanisms have been identified. These include not only processes associated with tumor, immune or stromal cells, but also humoral, metabolic, genetic and epigenetic factors within the TME. The identification of immune escape mechanisms has enabled the development of small molecules, nanomedicines, immune checkpoint inhibitors, adoptive cell and epigenetic therapies that can reprogram the TME and shift the host immune response towards promoting an antitumor effect. These approaches have translated into series of breakthroughs in cancer therapies, some of which have already been implemented in clinical practice. In the present article the authors provide an overview of some of the most important mechanisms of immunosuppression within the TME and the implications for targeted therapies against different cancers.

Elevated expression of cancer/testis antigen FSIP1 in ER-positive breast tumors.

AIM: The study aimed to identify and characterize highly specific breast tumor biomarkers. METHODS: A microarray data set comprised of 513 diverse normal and tumor mRNA samples was analyzed to identify breast tumor biomarkers with minimal expression in normal tissues. RESULTS: FSIP1 was identified as a breast tumor biomarker with elevated mRNA expression in breast tumors and minimal expression in most normal tissues except the testis. Quantitative real-time PCR confirmed the elevated expression of FSIP1 mRNA in breast tumors and revealed a significant correlation with ER-positive status. Immunofluorescence staining of breast tumor sections showed that the majority of breast tumors examined in this study (20 out of 22) expressed detectable FSIP1 protein, with significantly higher than average expression in ER-positive versus ER-negative breast tumors. CONCLUSION: The prevalence and uniformity of FSIP1 expression in breast tumors, taken together with the highly restricted expression in normal tissues, suggests that FSIP1 may be an attractive target for breast cancer immunotherapy.

COL10A1 expression is elevated in diverse solid tumor types and is associated with tumor vasculature.

AIM: The identification of molecular markers that are upregulated in multiple tumor types could lead to novel diagnostic and therapeutic strategies. The authors screened a panel of RNAs prepared from diverse tumors and tumor cell lines, and compared them with normal tissues and cultured somatic cell types, in order to identify candidate genes expressed in a broad spectrum of tumor types. MATERIALS & METHODS: Gene expression microarray analysis was carried out on 128 individual tumor samples representing over 20 tumor types, 85 samples representing 31 diverse normal tissue types, 68 tumor cell lines and 97 diverse normal primary cell cultures. Genes were ranked for elevated expression across a large number and variety of tumors relative to normal tissues. RESULTS & CONCLUSION: COL10A1 was identified as a gene with restricted expression in most normal tissues and elevated expression in many diverse tumor types. By contrast, COL10A1 expression was undetectable in the 68 tumor cell lines surveyed in this study. Immunofluorescence studies localized collagen, type X, α-1 (collagen X) staining to tumor vasculature in breast tumors, whereas the vasculature of normal breast tissue was either collagen X-negative or had markedly lower levels. The tumor microenvironment-specific expression of collagen X, together with its localization in the vasculature, may facilitate its use as a novel target for the diagnosis and treatment of diverse solid tumor types.