Sirtuin-1 deacetylates proteins and has emerged as a critical regulator of different cellular processes, particularly inflammation. Basal SIRT1 activity was previously found to limit Th9 and enhance Th17 differentiation in mice, but the effect of pharmacological SIRT1 activation on T cell differentiation and antitumor responses remains unclear. Here, we find that SIRT1 pharmacological agonists selectively impede mouse and human Th17 cell differentiation. SIRT1 activation induces STAT3 deacetylation, thus reducing its ability to translocate into the nucleus, bind to Rorc promoter, and induce its transcription. SIRT1 agonists reduce tumor growth in mice by blocking Th17 cell differentiation. In cancer patients, the SIRT1 agonist metformin reduced the frequency of Th17 cells and STAT3 acetylation levels. Altogether, these data underscore that SIRT1 activation impedes Th17 cell differentiation and thereby limits tumor growth and suggest that SIRT1 activators may directly target IL-17A functions.

With the rapid clinical development of immune checkpoint inhibitors (ICIs), the standard of care in cancer management has evolved rapidly. However, immunotherapy is not currently beneficial for all patients. In addition to intrinsic tumor factors, other etiologies of resistance to ICIs arise from the complex interplay between cancer and its microenvironment. Recognition of the essential role of the tumor microenvironment (TME) in cancer progression has led to a shift from a tumor-cell-centered view of cancer development, to the concept of a complex tumor ecosystem that supports tumor growth and metastatic dissemination. The expansion of immunosuppressive cells represents a cardinal strategy deployed by tumor cells to escape detection and elimination by the immune system. Regulatory T lymphocytes (Treg), myeloid-derived suppressor cells (MDSCs), and type-2 tumor-associated macrophages (TAM2) are major components of these inhibitory cellular networks, with the ability to suppress innate and adaptive anticancer immunity. They therefore represent major impediments to anticancer therapies, particularly immune-based interventions. Recent work has provided evidence that, beyond their direct cytotoxic effects on cancer cells, several conventional chemotherapeutic (CT) drugs and agents used in targeted therapies (TT) can promote the elimination or inactivation of suppressive immune cells, resulting in enhanced antitumor immunity. In this review, we will analyze findings pertaining to this concept, discuss the possible molecular bases underlying the selective targeting of these immunosuppressive cells by antineoplastic agents (CT and/or TT), and consider current challenges and future prospects related to the integration of these molecules into more efficient anticancer strategies, in the era of immunotherapy. Graphical abstract (Made with Biorender)

Thanks to their anti-inflammatory, anti-oedema, and anti-allergy properties, glucocorticoids are among the most widely prescribed drugs in patients with cancer. The indications for glucocorticoid use are very wide and varied in the context of cancer and include the symptomatic management of cancer-related symptoms (compression, pain, oedema, altered general state) but also prevention or treatment of common side effects of anti-cancer therapies (nausea, allergies, etc.) or immune-related adverse events (irAE). In this review, we first give an overview of the different clinical situations where glucocorticoids are used in oncology. Next, we describe the current state of knowledge regarding the effects of these molecules on immune response, in particular anti-tumour response, and we summarize available data evaluating how these effects may interfere with the efficacy of immunotherapy using immune checkpoint inhibitors.

Chemotherapy is initially used to kill proliferative cells. In the current area of emerging immunotherapy, chemotherapies have shown their ability to modulate the tumor micro environment and immune response. We focus here on two main effects: first, immunogenic cell death, defined as a form of regulated cell death (RCD) that is sufficient to activate an adaptive immune response in immunocompetent hosts; and second, the depletion of suppressive cells, known to play a major role in immune escape and resistance to immunotherapy. In this review, we present a review of different classically used chemotherapies focusing on this double effect on immunity. These immunological effects of chemotherapy could be exploited to promote efficacy of immunotherapy. Broadening our understanding will make it possible to provide rationales for the combination of chemoimmunotherapy in early clinical trials.

Background: Predictive biomarkers of response to chemotherapy plus antiangiogenic for metastatic colorectal cancer (mCRC) are lacking. The objective of this study was to test the prognostic role of splenomegaly on baseline CT scan. Methods: This study is a sub-study of PRODIGE-9 study, which included 488 mCRC patients treated by 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and bevacizumab in first line. The association between splenic volume, and PFS and OS was evaluated by univariate and multivariable Cox analyses. The relation between circulating monocytic Myeloid derived suppressor cells (mMDSC) and splenomegaly was also determined. Results: Baseline splenic volume > 180 mL was associated with poor PFS (median PFS = 9.2 versus 11.1 months; log-rank p = 0.0125), but was not statistically associated with OS (median OS = 22.6 versus 28.5 months; log-rank p = 0.1643). The increase in splenic volume at 3 months had no impact on PFS (HR 0.928; log-rank p = 0.56) or on OS (HR 0.843; log-rank p = 0.21). Baseline splenic volume was positively correlated with the level of baseline circulating mMDSC (r = 0.48, p-value = 0.031). Conclusion: Baseline splenomegaly is a prognostic biomarker in patients with mCRC treated with FOLFIRI and bevacizumab, and a surrogate marker of MDSC accumulation.