Sculpting tumor microenvironment with immune system: from immunometabolism to immunoediting

Abstract

Cancer immunotherapy unleashing the power of host immunity on eliminating cancer cells represents a critical advance in cancer treatment; however, effective anti-tumor responses are largely dampened by the immunosuppressive tumor microenvironment (TME). Emerging studies have revealed that physiological features in the TME, including glucose deprivation, hypoxia and low pH, established by the metabolically dysregulated cancer cells restrict anti-tumor immunity by impeding the metabolic fitness of tumor-infiltrating cytotoxic CD8 + T cells and natural killer (NK) cells. Furthermore, infiltrating immunomodulatory cells with different metabolic preferences also facilitate the establishment of the immunosuppressive TME. Therefore, deciphering the metabolic cross-talk between immune cells and cancer cells in the TME and elucidating the impact of this process during tumorigenesis are needed to harness anti-tumor immunity more effectively. Herein, we summarize the immunosuppressive features of TME and how these features impair anti-tumor immunity. Moreover, we postulate how immune cells may be involved in shaping the metabolic features of cancer cells and discuss how we might improve the anti-tumor functions of tumorspecific T cells by rewiring their metabolic regulations.

Fibronectin in Cancer: Friend or Foe

“…During early process of transformation, normal cells usually encounter various types of stresses, leading to premature cellular senescence that autonomously halts the continuous growth of damaged cells to prevent the occurrence of tumor and non-autonomously affects the surrounding microenvironments, including immune cell recruitment for eliminating the senescent cells (so called elimination stage of immunoediting during tumor progression) and stromal cell senescence for tissue remodeling [26,[107][108][109][110]. Cumulative evidence indicates that increased FN expression is a relatively common event in the senescent cells and even in the secretome of ASAP [111][112][113][114].…”

“…Conceptually, cells with pVHL-deficient may not properly assemble periFN on their surfaces but accumulate misfolded FN in the ER lumen, leading to unmanageable ER stress and premature cellular senescence [131]. Such senescent cells may be maintained in an equilibrium stage until they are able to significantly downregulate FN, reduce ER stress, evade the cellular senescence, and progress to the escape stage ( Figure 2) [26]. In line with the aforementioned idea of the molecular mechanism underlying cellular senescence escaping and tumor transformation, HSP90 chaperon proteins have been reported to be capable of binding to and guiding newly synthesized FN in the ER lumen of normal epithelial cells, facilitating proper folding of glycosylated FN structure followed by appropriate periFN assembly on cell surfaces [132,133].…”

“…The mutual interactions between parenchymal cells that endure the process of oncogenic stresses and transformation and stromal microenvironments harboring mesenchymal cells endow tumorigenesis and tumor progression [26,137]. In contrast to the significant downregulation of FN in tumor cells in primary tumor tissues, FN that is deposited in the ECM of TMEs plays an important role in promoting tumor progression, including tumor cell growth, migration, invasion, angiogenesis, and intravasation [13,[138][139][140][141][142][143][144][145][146][147][148].…”

Neutrophil extracellular trap formation correlates with improved overall survival in ovarian cancer

“…The tumor microenvironment, including the immune system, may have an important impact on tumor progression and treatment response [1,2]. Focussing on tumor-stroma interactions, we are applying molecular profiling via mass spectrometry (MS), especially by the combination of proteomics, lipidomics and metabolomics [3][4][5][6].…”

Translating immunometabolism: towards curing human diseases by targeting metabolic processes underpinning the immune response

“…Yu and Ho [4] describe how the tumour microenvironment (TME) impacts T cell metabolism and interlinked immune function, for example via nutrient restriction, increased immune checkpoint signalling, altered pH, metabolite accumulation and hypoxia. Furthermore, they describe novel therapeutic strategies aiming either to correct the immunosuppressive TME via targeting metabolic pathways and enzymes, or to rewire T cells themselves to increase their "metabolic tolerance".…”