PD-1 Blockade Reverses Obesity-Mediated T Cell Priming Impairment

Abstract

Despite obesity reaching pandemic proportions, its impact on antigen-specific T cell responses is still unclear. We have recently demonstrated that obesity results in increased expression of PD-1 on T cells, and checkpoint blockade targeting PD-1/PD-L1 surprisingly resulted in greater clinical efficacy in cancer therapy. Adverse events associated with this therapy center around autoimmune reactions. In this study, we examined the impact of obesity on T cell priming and on autoimmune pathogenesis using the mouse model experimental autoimmune encephalomyelitis (EAE), which is mediated by autoreactive myelin-specific T cells generated after immunization. We observed that diet-induced obese (DIO) mice had a markedly delayed EAE onset and developed milder clinical symptoms compared to mice on control diet (CD). This delay was associated with impaired generation of myelin-specific T cell numbers and concurrently correlated with increased PD-L1 upregulation on antigen-presenting cells in secondary lymphoid organs. PD-1 blockade during the priming stage of EAE restored disease onset and severity and increased numbers of pathogenic CD4+ T cells in the central nervous system (CNS) of DIO mice to similar levels to those of CD mice. Administration of anti-PD-1 after onset of clinical symptoms did not increase EAE pathogenesis demonstrating that initial priming is the critical juncture affected by obesity. These findings demonstrate that obesity impairs antigen-specific T cell priming, but this can be reversed with PD-1 blockade. Our results further suggest that PD-1 blockade may increase the risk of autoimmune toxicities, particularly in obesity.

The role of obesity and bariatric surgery-induced weight loss in breast cancer

“…However, a sometimes-complicated notion is that obesity also leads to compensatory immunosuppressive mechanisms to avoid a constant, full-blown pro-inflammatory response, similar controlling any immune reaction, to maintain homeostasis. These mechanisms include reduced absolute numbers of activated CD8 + T cells, T cell suppression by PD-1 [241,242], T cell exhaustion [243], and dysfunctional NK cells [244]. Thus, obesity induces a complex and dynamic state of pro-inflammatory immune cell content and function with an influx of monocyte-derived "M1"-like macrophages, combined with reductions in immunomodulatory/ regulatory or dysfunctional immune cells such as regulatory T cells (Tregs), "M2"-like macrophages, or NK Cells, together with an induction of checkpoint ligands (discussed below) [245][246][247][248], and elevated immunosuppressive cells such as immature monocytes or myeloid-derived suppressive cells (MDSCs) [249][250][251][252][253].…”

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“…These cells are characterized by reduced proliferative capacity and telomerase activity and show adverse metabolic changes. PD-1 blockade has been proposed as a therapeutic intervention, with a potential to enhance T cell priming in obese individuals [78], whereas senolytics (that induce senescent cell death), such as the CD153 vaccine, have been shown to ameliorate senescent T cells accumulation in adipose tissue in animal models [13].…”

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“…Obesity acts by impairing antigen-specific T-cell priming through PD-1/PD-L1 axis upregulation. Thus, PD-1 blockade in this setting results in both greater responsiveness and greater incidence of adverse reactions [ 117 ]. Interestingly, a real-life, multicenter, retrospective observational study involving more than one thousand patients has indeed revealed that higher body mass index was significantly related to the higher occurrence of any grade irAEs, grade 3 and grade 4 irAEs, and irAEs leading to treatment discontinuation [ 118 ].…”