CD98 at the crossroads of adaptive immunity and cancer

Abstract

SummaryAdaptive immunity, a vertebrate specialization, adds memory and exquisite specificity to the basic innate immune responses present in invertebrates while conserving metabolic resources. In adaptive immunity, antigenic challenge requires extremely rapid proliferation of rare antigen-specific lymphocytes to produce large, clonally expanded effector populations that neutralize pathogens. Rapid proliferation and resulting clonal expansion are dependent on CD98, a protein whose well-conserved orthologs appear restricted to vertebrates. Thus, CD98 supports lymphocyte clonal expansion to enable protective adaptive immunity, an advantage that could account for the presence of CD98 in vertebrates. CD98 supports lymphocyte clonal expansion by amplifying integrin signals that enable proliferation and prevent apoptosis. These integrin-dependent signals can also provoke cancer development and invasion, anchorage-independence and the rapid proliferation of tumor cells. CD98 is highly expressed in many cancers and contributes to formation of tumors in experimental models. Strikingly, vertebrates, which possess highly conserved CD98 proteins, CD98-binding integrins and adaptive immunity, also display propensity towards invasive and metastatic tumors. In this Commentary, we review the roles of CD98 in lymphocyte biology and cancer. We suggest that the CD98 amplification of integrin signaling in adaptive immunity provides survival benefits to vertebrates, which, in turn, bear the price of increased susceptibility to cancer.

CD98hc (SLC3A2) regulation of skin homeostasis wanes with age

“…Because most of the human malignancies arise in actively self-renovating sites of epithelial tissues (Sen et al, 2010), integrin signaling is thought to play an important role in formation and maintenance of epithelial cancers (White et al, 2004;Kass et al, 2007). Considering the physiological role of CD98hc in mammalian epithelial tissue formation and homeostasis, and the fact that enhanced expression of CD98hc epithelial neoplasias is indicative of malignant evolution (Cantor and Ginsberg, 2012), it could be hypothesized that novel studies on such a multifunctional protein would pave the way to new discoveries.…”

ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death

“…Rapid and extensive proliferation of T cells following encounter with 'danger' or antigenic stimulation (along with proper costimulation) 27 is one of the keystone functions of adaptive immunity. 28 This property is important for antitumor immunity 29 or tumor immunogenicity 30 such that inhibition of T cell proliferation causes tumoral immune resistance. 31 Interestingly, IFNG-production from T cells, which is crucial for the immunogenicity of cancer cells, 11,13 has been shown recently to be strongly reduced when autophagy was ablated in cancer cells undergoing ICD.…”

Antitumor activity of an anti‐CD98 antibody

“…3,7 The function of CD98 in regulating both amino acid transport and integrin signaling can contribute to the rapid proliferation and clonal expansion of lymphocytes and tumor cells. 3 The expression pattern and pleiotropic function of CD98 heavy and light chains suggest these proteins are promising targets for treatment of a variety of human cancers. Although small molecule inhibitors of LAT-1 activity have demonstrated preclinical antitumor activity in a number of cancer cell types, including NSCLC, colon cancer, oral cancer and breast cancer, development of antibodies against CD98 heavy chain has received less focus.…”

“…1,2 CD98 is overexpressed on the cell surface of almost all tumor cells, regardless of tissue origin and increased expression of a CD98-light chain, L-type amino acid transporter 1 (LAT-1) occurs in many types of human cancers, including breast, colon, oral, ovarian, esophageal, glioma and leukemia. 3,4 Increased uptake of amino acids supports the high growth rate of cancer cells by providing the building blocks for protein synthesis. [4][5][6] Moreover, the higher expression of CD98 heavy chain and LAT-1 in metastatic vs. primary tumors suggests that over-expression of CD98/LAT-1 may facilitate progression and metastasis of human cancers.…”

“…3,7 The function of CD98 in regulating both amino acid transport and integrin signaling can contribute to the rapid proliferation and clonal expansion of lymphocytes and tumor cells. 3 The expression pattern and pleiotropic function of CD98 heavy and light chains suggest these proteins are promising targets for treatment of a variety of human cancers.…”