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Review
. 2023 Dec 9;22(1):201.
doi: 10.1186/s12943-023-01893-w.

Exploiting autophagy balance in T and NK cells as a new strategy to implement adoptive cell therapies

Manuela Giansanti #  1 , Tobias Theinert #  2 , Sarah Katharina Boeing  2 , Dorothee Haas  2 , Paul-Gerhardt Schlegel  2 , Paola Vacca  1 , Francesca Nazio #  3   4 , Ignazio Caruana #  5
Affiliations
Review

Exploiting autophagy balance in T and NK cells as a new strategy to implement adoptive cell therapies

Manuela Giansanti et al. Mol Cancer. .

Abstract

Autophagy is an essential cellular homeostasis pathway initiated by multiple stimuli ranging from nutrient deprivation to viral infection, playing a key role in human health and disease. At present, a growing number of evidence suggests a role of autophagy as a primitive innate immune form of defense for eukaryotic cells, interacting with components of innate immune signaling pathways and regulating thymic selection, antigen presentation, cytokine production and T/NK cell homeostasis. In cancer, autophagy is intimately involved in the immunological control of tumor progression and response to therapy. However, very little is known about the role and impact of autophagy in T and NK cells, the main players in the active fight against infections and tumors. Important questions are emerging: what role does autophagy play on T/NK cells? Could its modulation lead to any advantages? Could specific targeting of autophagy on tumor cells (blocking) and T/NK cells (activation) be a new intervention strategy? In this review, we debate preclinical studies that have identified autophagy as a key regulator of immune responses by modulating the functions of different immune cells and discuss the redundancy or diversity among the subpopulations of both T and NK cells in physiologic context and in cancer.

Keywords: Autophagy; Effector cells; Metabolism; Mitophagy; T and NK development.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Primary types of autophagy: a schematic overview. Macroautophagy involves the regulation of Unc-51-like kinase 1 (ULK1) complex by both AMPK and mTOR. This complex mediates the initial stage of double-membrane scaffold formation around the autophagy cargo by recruiting the Beclin1-Vps34 complex in the proximity of the phagophore. In the next step of elongation, ATG7-ATG3 and ATG5-ATG12-ATG6L1 complexes mediate the conjugation of lipidated microtubule-associated protein 1A/1B light chain 3 (LC3I) family members with phosphatidylethanolamine (LC3II). Mature autophagosomes fuse with lysosome to form the autophagolysosome, in which autophagic cargo is degraded and recycled. Selective autophagy leads to the degradation of damaged organelles (e.g., pexophagy, ribophagy, lysophagy) or substrates (e.g. aggrephagy, fluidophagy, lipophagy) through the binding of selective receptors with autophagy core proteins (LC3B, GABARAP). Chaperone-mediated autophagy (CMA) is a form of autophagy in which cytoplasmic KFERQ motif proteins are recruited by the Hsc70 chaperone complex. It, then, binds to the lysosome-associated membrane protein type 2 isoform A (LAMP-2A) on the lysosome membrane, which undergoes oligomerization to form a transport channer that mediates the translocation of protein cargo into lysosome for its degradation. Microautophagy, instead, mediates a non-selective up-take of cytoplasmic cargo through invagination (or protrusion) of lysosome membrane. The figure is created with “BioRender.com”
Fig. 2
Fig. 2
Autophagy and T cell development. Hematopoietic stem cells (HSCs) arise in the bone marrow (BM) and migrate into the peripheral blood circulation as common lymphoid progenitors (CLP), finally reaching the thymus tissue. In the cortical section of the thymic lobule, double negative (DN) thymocytes lacking CD4 and CD8 develop into double positive (DP) cells. By interaction with peptide-loaded MHC (pMHC) complexes of cortical thymic epithelial cells (cTECs) ensuring the functionality upon MHC stimulation, thymocytes are positively selected. In the medullary part of the lobule, thymocytes are negatively selected by the interaction with pMHC ligands on medullary thymic epithelial cells (mTEC) and antigen-presenting cells (APC) to filter out and exclude self-reactive T-cells. After selection, thymocytes undergo commitment to the CD4, CD8, or NK-T lineage to single positive (SP) cells and are released into the bloodstream as naïve T cells. Depending on interaction with class II MHC complexes and cytokines milieu, CD4+ cells differentiate into further subsets. The figure is created with “BioRender.com”
Fig. 3
Fig. 3
Autophagy and T cell activation. When T cells are activated by TCR-stimulation and co-stimulation, these cells undergo a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis to meet the new enhanced metabolic requirements. Furthermore, this activation induces important transcriptional and translational changes mainly driven by mTOR-independent autophagy induction capable to activate and modulate the autophagy machinery. Activation-induced autophagy then contributes to: modulation of cytokine signalling and release; mediation of antioxidant effects; promotion of T cell survival and proliferation as well as sufficient ATP production and energy supply; control of intracellular calcium levels and calcium-dependent signalling; active impact on T cell fate by determining T cell differentiation and phenotype; modulation of mitochondrial respiration and glycolysis; influencing T cell function; impact on T cell cell-cycle control; modulation of cellular levels of specific T cell activation-related signalling players/autophagosomal cargo (Cyclin-dependent kinase inhibitor 1B (CDKN1B), itchy E3 ubiquitin protein ligase (Itch) and Regulator Of Calcineurin 1 (RCAN1), Interleukin-7 receptor subunit alpha (Il-7Rα), transcription factor PU.1, Protein Tyrosine Phosphatase Non-Receptor Type 1 (PTPN1), B-cell lymphoma/leukaemia 10 (Bcl-10), “selective exclusion” of mitochondria from autophagosomes). The figure is created with “BioRender.com”
Fig. 4
Fig. 4
Autophagy in NK cell development and functionality. The autophagy process drives Hematopoietic Stem Cell (HSCs) differentiation into Common Lymphoid Precursors (CLP) and gains less importance in the generation of NK cell Precursors (NKP). In the stage of immature NK cells (iNK), phosphorylation of Forkhead box O (FoxO) 1 protein mediates its translocation from the nucleus to the cytosol and induces autophagy through interaction with ATG7 in the phagophore. FoxO1 is lost in mature NK cells (mNK) and autophagy is effectively reduced (green lines follow the role of autophagy in NK cell development). At steady state (freshly isolated NK cells), both phenotypes of mNK cells exhibit lower autophagy at the basal level, tubular mitochondria, and dependence on glycolysis and OXPHOS for their metabolism. After activation, the metabolism of the immunomodulatory phenotype (CD56bright/CD16dim) does not undergo metabolic reprogramming and shows greater dependence on OXPHOS than glycolysis. On the other hand, activation of cytotoxic phenotype (CD56dim/CD16.bright) induces metabolic reprogramming to fuel cytolytic activities, and glycolysis gains more importance after NK-activating Receptors (NKRs)-mediated activation, while OXPHOS and citrate-malate shuttle fuel cytokines-mediated activation. In this context, autophagy is reduced during the proliferation stage of activated NK cells, and metabolic reprogramming is supported by DRP1-mediated mitochondrial fragmentation. In the latter stages of activation, fragmented mitochondria can be recycled through BNIP3/BNIP3L-mediated mitophagy to generate memory NK cells, and OPA-1-mediates mitochondrial fusion for their biogenesis. Fragmented mitochondria alter metabolic fitness in the absence of mitophagy, leading to apoptosis of NK cells. The figure is created with “BioRender.com”
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