Abstract
SummaryDepleting the microenvironment of important nutrients such as arginine is a key strategy for immune evasion by cancer cells. Many tumors overexpress arginase, but it is unclear how these cancers, but not T cells, tolerate arginine depletion. In this study, we show that tumor cells synthesize arginine from citrulline by upregulating argininosuccinate synthetase 1 (ASS1). Under arginine starvation, ASS1 transcription is induced by ATF4 and CEBPβ binding to an enhancer within ASS1. T cells cannot induce ASS1, despite the presence of active ATF4 and CEBPβ, as the gene is repressed. Arginine starvation drives global chromatin compaction and repressive histone methylation, which disrupts ATF4/CEBPβ binding and target gene transcription. We find that T cell activation is impaired in arginine-depleted conditions, with significant metabolic perturbation linked to incomplete chromatin remodeling and misregulation of key genes. Our results highlight a T cell behavior mediated by nutritional stress, exploited by cancer cells to enable pathological immune evasion.
Highlights
The concept of cancer immunosurveillance has been cemented with the success of immune checkpoint inhibitors (Dunn et al, 2004; Hamid et al, 2013; Hodi et al, 2010; Kim et al, 2007; Topalian et al, 2012; Wolchok et al, 2013)
No proliferation was observed under arginine starvation, and this was not rescued by addition of the arginine precursor citrulline (Figure 1A)
As CD25, a late T cell activation marker, was upregulated in T cells stimulated in ÀArg medium (Figure S1A)
Summary
The concept of cancer immunosurveillance has been cemented with the success of immune checkpoint inhibitors (Dunn et al, 2004; Hamid et al, 2013; Hodi et al, 2010; Kim et al, 2007; Topalian et al, 2012; Wolchok et al, 2013). The host immune system can detect and respond to tumors (Gajewski et al, 2013; Hadrup et al, 2013; Schreiber et al, 2011), and infiltration of tumors by T cells predicts a better clinical outcome (Galon et al, 2006). Evasion of the anti-tumor immune response is a hallmark of cancer, and tumors have evolved strategies to achieve this (Hanahan and Weinberg, 2011; Spranger and Gajewski, 2018; Wellenstein and de Visser, 2018). As a semi-essential amino acid, arginine availability is important in determining the immune system’s ability to respond to cancer. Depletion of arginine is a significant regulator of immune activity in various physiological and pathological circumstances, including pregnancy, the response to infectious agents, autoimmune disease, and cancer, dictating T cell growth and activity (Munder et al., Cell Reports 35, 109101, May 11, 2021 a 2021 The Author(s).
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