Editorial: CAR T-cells: novel therapeutic approaches in the new era of cancer immunotherapy

Immunotherapy has emerged as one of the most effective treatments capable of overcoming tumor resistance mechanisms due to its ability to modulate the patient’s immune response against cancer. Personalized anti-tumor therapy based on T cells engineered to express a cancer-specific chimeric antigen receptor (CAR) acts directly on the immune system of patients. Specifically, this therapy enhances the recognition of cancer cells by T lymphocytes, thus promoting their elimination. In this Research Topic several aspects of CAR T-cell therapy, with particular emphasis on novel findings aimed at ameliorating the effectiveness of CAR T-cell-based immunotherapy and reducing side effects, are described (Figure 1)

An observational study on chronic pain biomarkers in fibromyalgia and osteoarthritis patients:.which role for mu opioid receptor’s expression on NK cells.

The evaluation of chronic pain is challenging because of the lack of specific biomarkers. We identified the Mu opioid receptor-positive (Mu+) B cell percentage of expression, named Mu-Lympho-Marker (MLM), as a candidate marker for chronic pain in fibromyalgia (FM) and osteoarthritis (OA) patients. Here, we investigate the role of MLM on natural killer (NK) cells in the same patients. Twenty-nine FM and twelve OA patients were analyzed, and twenty-three pain-free subjects were considered as the control group. Blood samples were collected to perform immunophenotyping and Western blot analysis. Biological and clinical data were statistically analyzed. The final results showed that the percentage of NK cells expressing Mu was statistically lower in FM and OA patients than in pain-free subjects, as already demonstrated for B cells. A Western blot analysis was performed in order to detect NK cells' functional status. Moreover, the correlation analysis of MLM expression with pharmacological therapy did not show any significant results. In conclusion, here, we confirm the role of MLM as a suitable marker for chronic pain and underline NK cells as a new possible immune cell type involved in the "Mu opioid receptor reserve theory"

Iron and Ferritin Modulate MHC Class I Expression and NK Cell Recognition

The ability of pathogens to sequester iron from their host cells and proteins affects their virulence. Moreover, iron is required for various innate host defense mechanisms as well as for acquired immune responses. Therefore, intracellular iron concentration may influence the interplay between pathogens and immune system. Here, we investigated whether changes in iron concentrations and intracellular ferritin heavy chain (FTH) abundance may modulate the expression of Major Histocompatibility Complex molecules (MHC), and susceptibility to Natural Killer (NK) cell cytotoxicity. FTH downregulation, either by shRNA transfection or iron chelation, led to MHC surface reduction in primary cancer cells and macrophages. On the contrary, mouse embryonic fibroblasts (MEFs) from NCOA4 null mice accumulated FTH for ferritinophagy impairment and displayed MHC class I cell surface overexpression. Low iron concentration, but not FTH, interfered with IFN-γ receptor signaling, preventing the increase of MHC-class I molecules on the membrane by obstructing STAT1 phosphorylation and nuclear translocation. Finally, iron depletion and FTH downregulation increased the target susceptibility of both primary cancer cells and macrophages to NK cell recognition. In conclusion, the reduction of iron and FTH may influence the expression of MHC class I molecules leading to NK cells activation

Helper Innate Lymphoid Cells—Unappreciated Players in Melanoma Therapy

Immune checkpoint inhibitors (ICIs) and targeted therapy have dramatically changed the outcome of metastatic melanoma patients. Although immune checkpoints were developed based on the biology of adaptive T cells, they have subsequently been shown to be expressed by other subsets of immune cells. Similarly, the immunomodulatory properties of targeted therapy have been studied primarily with respect to T lymphocytes, but other subsets of immune cells could be affected. Innate lymphoid cells (ILCs) are considered the innate counterpart of T lymphocytes and include cytotoxic natural killer cells, as well as three helper subsets, ILC1, ILC2 and ILC3. Thanks to their tissue distribution and their ability to respond rapidly to environmental stimuli, ILCs play a central role in shaping immunity. While the role of NK cells in melanoma physiopathology and therapy is well established, little is known about the other helper ILC subsets. In this review, we summarize recent findings on the ability of the melanoma TME to influence the phenotype and functional plasticity of helper ILCs and highlight how this subset may in turn shape the TME. We also discuss changes in the melanoma TME induced by targeted therapy that could affect helper ILC functions, the expression of immune checkpoints on this subset and how their inhibition by ICIs may modulate helper ILC function and contribute to therapeutic efficacy

Altered Frequencies and Functions of Innate Lymphoid Cells in Melanoma Patients Are Modulated by Immune Checkpoints Inhibitors

Monoclonal antibodies targeting immune checkpoints improved clinical outcome of patients with malignant melanoma. However, the mechanisms are not fully elucidated. Since immune check-point receptors are also expressed by helper innate lymphoid cells (ILCs), we investigated the capability of immune checkpoints inhibitors to modulate ILCs in metastatic melanoma patients as well as melanoma cells effects on ILC functions. Here, we demonstrated that, compared to healthy donors, patients showed a higher frequency of total peripheral ILCs, lower percentages of CD117+ ILC2s and CD117+ ILCs as well as higher frequencies of CD117- ILCs. Functionally, melanoma patients also displayed an impaired TNFα secretion by CD117- ILCs and CD117+ ILCs. Nivolumab therapy reduced the frequency of total peripheral ILCs but increased the percentage of CD117- ILC2s and enhanced the capability of ILC2s and CD117+ ILCs to secrete IL-13 and TNFα, respectively. Before Nivolumab therapy, high CCL2 serum levels were associated with longer Overall Survival and Progression Free Survival. After two months of treatment, CD117- ILC2s frequency as well as serum concentrations of IL-6, CXCL8 and VEGF negatively correlated with both the parameters. Moreover, melanoma cells boosted TNFα production in all ILC subsets and increased the number of IL-13 producing ILC2s in vitro. Our work shows for the first time that PD-1 blockade is able to affect ILCs proportions and functions in melanoma patients and that a specific subpopulation is associated with the therapy response

Accumulation of Circulating CCR7+ Natural Killer Cells Marks Melanoma Evolution and Reveals a CCL19-Dependent Metastatic Pathway

none23siImmune checkpoint blockade therapy has changed prognoses for many melanoma patients. However, immune responses that correlate with clinical progression of the disease are still poorly understood. To identify immune responses correlating with melanoma clinical evolution, we analyzed serum cytokines as well as circulating NK and T-cell subpopulations from melanoma patients. The patients' immune profiles suggested that melanoma progression leads to changes in peripheral blood NK and T-cell subsets. Stage IV melanoma was characterized by an increased frequency of CCR7+CD56bright NK cells as well as high serum concentrations of the CCR7 ligand CCL19. CCR7 expression and CCL19 secretion were also observed in melanoma cell lines. The CCR7+ melanoma cell subpopulation coexpressed PD-L1 and Galectin-9 and had stemness properties. Analysis of melanoma-derived cancer stem cells (CSC) showed high CCR7 expression; these CSCs were efficiently recognized and killed by NK cells. An accumulation of CCR7+, PD-L1+, and Galectin-9+ melanoma cells in melanoma metastases was demonstrated ex vivo Altogether, our data identify biomarkers that may mark a CCR7-driven metastatic melanoma pathway.mixedCristiani, Costanza Maria; Turdo, Alice; Ventura, Valeria; Apuzzo, Tiziana; Capone, Mariaelena; Madonna, Gabriele; Mallardo, Domenico; Garofalo, Cinzia; Giovannone, Emilia Dora; Grimaldi, Antonio M; Tallerico, Rossana; Marcenaro, Emanuela; Pesce, Silvia; Zotto, Genny Del; Agosti, Valter; Costanzo, Francesco Saverio; Gulletta, Elio; Rizzo, Aroldo; Moretta, Alessandro; Karre, Klas; Ascierto, Paolo A; Todaro, Matilde; Carbone, EnnioCristiani, Costanza Maria; Turdo, Alice; Ventura, Valeria; Apuzzo, Tiziana; Capone, Mariaelena; Madonna, Gabriele; Mallardo, Domenico; Garofalo, Cinzia; Giovannone, Emilia Dora; Grimaldi, Antonio M; Tallerico, Rossana; Marcenaro, Emanuela; Pesce, Silvia; Zotto, Genny Del; Agosti, Valter; Costanzo, Francesco Saverio; Gulletta, Elio; Rizzo, Aroldo; Moretta, Alessandro; Karre, Klas; Ascierto, Paolo A; Todaro, Matilde; Carbone, Enni