Blocking inflammation to improve immunotherapy of advanced cancer

Abstract

The ability to induce functional reprogramming of regulatory T (Treg) cells in the tumor microenvironment is an extremely important therapeutic opportunity. However, when discussing such an approach, the opposing effect that the activation of the Treg cell compartments may have in inducing the immune inflammatory response and its link with the efficacy of immunotherapy should be considered. In fact, Treg reprogramming has a dual effect: immediate, with mechanisms that activate immunosurveillance, and late, mediated by the macrophage activation that yields an inflammatory status that is deleterious for the antineoplastic efficiency of the immune system response. Persistence of the inflammatory response is associated with specific changes of oxidative and glycolytic metabolic pathways that interfere with conventional T‐cell activation and function and may be one of the reasons for the failure of immunotherapy in advanced cancer patients. Therefore, in addition to modulating Treg cell action, the combined use of drugs able to block chronic inflammation mediated mainly by macrophages, to counteract the oxidative stress, and to positively regulate the metabolic derangements, could improve the effectiveness of modern immunotherapy. In conclusion, reprogramming of Treg cells may be an appropriate strategy for treating early stages of neoplastic diseases, whereas other immunosuppressive mechanisms should be the target of a combined immunotherapy approach in more advanced phases of cancer.

Bioinformatic screening and identification of downregulated hub genes in adrenocortical carcinoma

“…However, the concrete inflammatory regulatory mechanisms of DEGs relied on further research. In summary, the enrichment analysis results of the current study are consistent with previous oncology research (12,21).…”

COVID-19 and cytokine storm syndrome: can what we know about interleukin-6 in ovarian cancer be applied?

“…Next, active replication of SARS-COV likely induces a delayed type I IFN response resulting in compromised early viral control and increased influx of pro-inflammatory macrophages [ 66 , 70 ]. At this point, all events associated with aspecific chronic inflammation become activated; therefore, the persistence of the virus and the activation of innate immunity result in excessive, prolonged nonspecific inflammation, which negatively impacts immunosurveillance [ 71 ]. These events are similar to those described ovarian cancer microenvironment and contribute to the well-known phenomena of immune editing and escape in cancer development [ 71 , 72 ].…”

“…In summary, macrophages are essential elements during the initial phase of the immune response, due to their antiviral properties, capacity to synthesize IFN, and interactions with, and recruitment of, helper and cytotoxic T lymphocytes. However, their persistent activation leads to the impairment of effective T-cell responses by causing T-cell exhaustion, a condition where the lymphocytes, even when activated, are nonfunctional and subsequently undergo programmed cell death [ 71 , 73 ], which may contribute to the observed lymphopenia in COVID-19. Recently, we have highlighted how blocking chronic inflammation, primarily driven by IL-6, may improve the efficacy of the currently available immunotherapy in cancer patients [ 71 ].…”

“…Other negative effects exerted by IL-6 on the immune system result from its regulation of cellular glucose uptake, glycolysis, and iron trafficking. IL-6 disrupts energy and iron metabolism, leading to T-cell exhaustion, characterized by a progressive loss of T-cell function [ 71 ]. IL-6 can also exert direct inhibitory effects on the PI3K/Akt/ mTOR pathway, thereby inhibiting primary cellular energetic and anabolic processes [ 109 ].…”

“…Moreover, we have shown, in a large cohort of patients with advanced cancer evaluated at diagnosis before any antineoplastic treatment, where ovarian cancer patients showed the most severe anemia, that IL-6 correlated directly with the Glasgow Prognostic Score an inflammatory/nutritional index defined by the CRP/albumin ratio [ 30 ]. Overall, IL-6 signaling can cause an energy deficiency condition that represses T-cell receptor (TCR)-related signaling, IFN production, cytotoxicity, and T-cell motility, with detrimental effects on the immune response [ 71 ]. Thus, inflammatory immune response can deplete T cells and affecting the outcomes of patient with COVID-19 leaving them prone to secondary infection [ 110 ].…”