Metabolic Modifications, Inflammation, and Cancer Immunotherapy

Abstract

Cancer immunotherapy has accomplished significant progresses on treatment of various cancers in the past decade; however, recent studies revealed more and more heterogeneity in tumor microenvironment which cause unneglectable therapy resistance. A central phenomenon in tumor malignancy is metabolic dysfunctionality; it reprograms metabolic homeostasis in tumor and stromal cells thus affecting metabolic modifications on specific proteins. These posttranslational modifications include glycosylation and palmitoylation, which usually alter the protein localization, stability, and function. Many of these proteins participate in acute or chronic inflammation and play critical roles in tumorigenesis and progression. Therefore, targeting these metabolic modifications in immune checkpoints and inflammation provides an attractive therapeutic strategy for certain cancers. In this review, we summarize the recent progresses on metabolic modifications in this field, focus on the mechanisms on how glycosylation and palmitoylation regulate innate immune and inflammation, and we further discuss designing new immunotherapy targeting metabolic modifications. We aim to improve immunotherapy or targeted-therapy response and achieve more accurate individual therapy.

Keywords: PD-1/PD-L1; cancer immunotherapy; glycosylation; inflammation; metabolic modifications; palmitoylation.

Figure 1

The roles of glycosylation and palmitoylation of PD-1/PD-L1. In T cells, PD-1 is glycosylated by FUT8, leading to its stable expression on the cell surface and causing a stronger interaction with glycosylated PD-L1. On the other hand, PD-L1 is glycosylated or degraded through different pathways. It can be glycosylated by STT3 in ER or by B3GNT3 in the Golgi apparatus. Glycosylation helps to maintain its stability by preventing GSK3β-dependent phosphorylation and downstream β-Trcp-mediated 26S proteasome degradation. In addition, PD-L1 palmitoylation catalyzed by ZDHHC3 stabilizes PD-L1 through blocking PD-L1 mono-ubiquitination, otherwise ubiquitinated PD-L1 will be sorted by endosomal sorting complexes required for transport (ESCRT) to the multivesicular body (MVB) for degradation. Glycosylation is affected by the branch glucose metabolism pathway HBP, which directly provides the glycosylation substrate (UDP)-GlcNAc. Palmitoylation is affected by the lipid synthesis which leads to palmitate acid storage.

Figure 2

The roles of palmitoylation in inflammation. Palmitoylation affects inflammatory response in many ways. MYD88 is palmitoylated by ZDHHC6, facilitating downstream NF-κB inflammation pathway activation by mediating association with IRAF-4. NOD1/2 is palmitoylated by ZDHHC5, which is required for membrane recruitment and downstream signaling. Five palmitoyl-transferases (localized at different cell compartments including ER and Golgi apparatus) positively regulate STING-dependent inflammatory response. The STAT3 palmitoylation–depalmitoylation cycle, catalyzed by DHHC7 and APT2, controls phosphorylation of STAT3 by JAK2 and contributes to STAT3 nuclear translocation, which is essential for IL-17–induced inflammation.