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Published in final edited form as: J Bone Miner Res. 2014 Mar;29(3):749–760. doi: 10.1002/jbmr.2070

Abstract

Pseudohypoparathyroidism type-Ia (PHP-Ia), characterized by renal proximal tubular resistance to parathyroid hormone (PTH), results from maternal mutations of GNAS that lead to loss of Gαs activity. Gαs expression is paternally silenced in the renal proximal tubule, and this genomic event is critical for the development of PTH-resistance, as patients display impaired hormone action only if the mutation is inherited maternally. The primary clinical finding of PHP-Ia is hypocalcemia, which can lead to various neuromuscular defects including seizures. PHP-Ia patients frequently do not present with hypocalcemia until after infancy, but it has remained uncertain whether PTH-resistance occurs in a delayed fashion. Analyzing reported cases of PHP-Ia with documented GNAS mutations and mice heterozygous for disruption of Gnas, we herein determined that the manifestation of PTH-resistance caused by the maternal loss of Gαs, i.e. hypocalcemia and elevated serum PTH, occurs after early postnatal life. To investigate whether this delay could reflect gradual development of paternal Gαs silencing, we then analyzed renal proximal tubules isolated by laser capture microdissection from mice with either maternal or paternal disruption of Gnas. Our results revealed that, whereas expression of Gαs mRNA in this tissue is predominantly from the maternal Gnas allele at weaning (three-weeks postnatal) and in adulthood, the contributions of the maternal and paternal Gnas alleles to Gαs mRNA expression are equal at postnatal day 3. In contrast, we found that paternal Gαs expression is already markedly repressed in brown adipose tissue at birth. Thus, the mechanisms silencing the paternal Gαs allele in renal proximal tubules are not operational during early postnatal development, and this finding correlates well with

The diversity of infiltrating stromal cells occurring in human cancers exceeds 30 distinct subgroups, reflecting the huge complexity of the tumor microenvironment (TME), thereby deeply affecting the treatment option for each patient [1]. Attempts have been made to distill this out-of-order situation into a unifying method to better describe actual composition of the TME using both multi-omics and experimental technologies, shedding light on cancer biology. This trend led to a transition in cancer treatment from only targeting tumor cells (like traditional chemotherapy and radiotherapy) to a new generation of approaches emphasizing the modulation of endogenous immune response toward cancer.

The immune system can be generally divided into the innate and adaptive immune systems, both contributing to the recognition and removal of foreign pathogens as well as tumors [2]. Adaptive immunity is mainly composed of cells represented by T and B lymphocytes, which harbor an enormous repertoire of T-cell and B-cell receptors, respectively, that can respond specifically to different antigens in the body. Current immunotherapeutic methods mainly focus on T lymphocytes, especially restoring exhausted CD8 cytotoxic T cells (CTLs). An example of such approach is immune-checkpoint blockade, with blocking of receptors or ligands that inhibit the activation of CTLs, including programmed cell death protein 1 (PD-1), its main ligand PD-L1, cytotoxic T-lymphocyte antigen 4 (CTLA-4) and lymphocyte-activation gene-3 (LAG-3), by monoclonal neutralizing antibodies [3, 4]. In recent years, the rapid and potent anti-tumor function of innate immunity, which even occurs at a very early stage of tumor progression, has attracted increasing attention. As a subset of whole innate lymphoid cells, natural killer (NK) cells, defined by Herberman in 1976 [5] and often considered a part of type 1 innate-like cells (ILC1s), are currently defined as