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Adoptive transfer of T cells genetically engineered to express chimeric antigen receptors (CAR) has demonstrated striking efficacy for the treatment of several hematological malignancies, including B-cell lymphoma, leukemia, and multiple myeloma. However, many patients still do not respond to this therapy or eventually relapse after an initial remission. In most solid tumors for which CAR T-cell therapy has been tested, efficacy has been very limited. In this context, it is of paramount importance to understand the mechanisms of tumor resistance to CAR T cells. Possible factors contributing to such resistance have been identified, including inherent CAR T-cell dysfunction, the presence of an immunosuppressive tumor microenvironment, and tumor-intrinsic factors. To control tumor growth, CAR T cells have to migrate actively enabling a productive conjugate with their targets. To date, many cells and factors contained within the tumor microenvironment have been reported to negatively control the migration of T cells and their ability to reach cancer cells. Recent evidence suggests that additional determinants, such as immune checkpoint proteins, cellular metabolism, and adhesion molecules, may modulate the motility of CAR T cells in tumors. Here, we review the potential impact of these determinants on CAR T-cell motility, and we discuss possible strategies to restore intratumoral T-cell migration with a special emphasis on approaches targeting these determinants. [ABSTRACT FROM AUTHOR]

Simple Summary: We propose that PFK1 promotes a positive feedback loop with PI3K/AKT and YAP/TAZ signaling pathways in cancer cells. Therefore, targeting PFK1 (or its product F-1,6-BP) could improve the efficacy of PI3K and YAP/TAZ inhibitors currently tested in clinical trials. To this aim, we suggest the use of citrate, which is a physiologic and potent inhibitor of PFK1. PI3K/AKT is one of the most frequently altered signaling pathways in human cancers, supporting the activation of many proteins sustaining cell metabolism, proliferation, and aggressiveness. Another important pathway frequently altered in cancer cells is the one regulating the YAP/TAZ transcriptional coactivators, which promote the expression of genes sustaining aerobic glycolysis (such as WNT, MYC, HIF-1), EMT, and drug resistance. Of note, the PI3K/AKT pathway can also regulate the YAP/TAZ one. Unfortunately, although PI3K and YAP inhibitors are currently tested in highly resistant cancers (both solid and hematologic ones), several resistance mechanisms may arise. Resistance mechanisms to PI3K inhibitors may involve the stimulation of alternative pathways (such as RAS, HER, IGFR/AKT), the inactivation of PTEN (the physiologic inhibitor of PI3K), and the expression of anti-apoptotic Bcl-xL and MCL1 proteins. Therefore, it is important to improve current therapeutic strategies to overcome these limitations. Here, we want to highlight how the glycolytic enzyme PFK1 (and its product F-1,6-BP) promotes the activation of both PI3K/AKT and YAP/TAZ pathways by several direct and indirect mechanisms. In turn, PI3K/AKT and YAP/TAZ can promote PFK1 activity and F-1,6-BP production in a positive feedback loop, thus sustaining the Warburg effect and drug resistance. Thus, we propose that the inhibition of PFK1 (and of its key activator PFK2/PFKFB3) could potentiate the sensitivity to PI3K and YAP inhibitors currently tested. Awaiting the development of non-toxic inhibitors of these enzymes, we propose to test the administration of citrate at a high dosage, because citrate is a physiologic inhibitor of both PFK1 and PFK2/PFKFB3. Consistently, in various cultured cancer cells (including melanoma, sarcoma, hematologic, and epithelial cancer cells), this "citrate strategy" efficiently inhibits the IGFR1/AKT pathway, promotes PTEN activity, reduces Bcl-xL and MCL1 expression, and increases sensitivity to standard chemotherapy. It also inhibits the development of sarcoma, pancreatic, mammary HER+ and lung RAS-driven tumors in mice without apparent toxicities. [ABSTRACT FROM AUTHOR]

Citrate plays a central role in cancer cells' metabolism and regulation. Derived from mitochondrial synthesis and/or carboxylation of α-ketoglutarate, it is cleaved by ATP-citrate lyase into acetyl-CoA and oxaloacetate. The rapid turnover of these molecules in proliferative cancer cells maintains a low-level of citrate, precluding its retro-inhibition on glycolytic enzymes. In cancer cells relying on glycolysis, this regulation helps sustain the Warburg effect. In those relying on an oxidative metabolism, fatty acid β-oxidation sustains a high production of citrate, which is still rapidly converted into acetyl-CoA and oxaloacetate, this latter molecule sustaining nucleotide synthesis and gluconeogenesis. Therefore, citrate levels are rarely high in cancer cells. Resistance of cancer cells to targeted therapies, such as tyrosine kinase inhibitors (TKIs), is frequently sustained by aerobic glycolysis and its key oncogenic drivers, such as Ras and its downstream effectors MAPK/ERK and PI3K/Akt. Remarkably, in preclinical cancer models, the administration of high doses of citrate showed various anti-cancer effects, such as the inhibition of glycolysis, the promotion of cytotoxic drugs sensibility and apoptosis, the neutralization of extracellular acidity, and the inhibition of tumors growth and of key signalling pathways (in particular, the IGF-1R/AKT pathway). Therefore, these preclinical results support the testing of the citrate strategy in clinical trials to counteract key oncogenic drivers sustaining cancer development and resistance to anti-cancer therapies. [ABSTRACT FROM AUTHOR]

Lower pre-surgery Body Mass Index (BMI) and low muscle mass impact negatively long-term survival of non-small cell lung cancer (NSCLC). We investigated their influence on survival after major lung resection for NSCLC. Methods: A retrospective analysis of a prospectively collected database was made on 304 consecutive patients. Results: Underweight, normal, overweight and obese patients represented 7.6%, 51.6%, 28.6%, and 12.6% of the pre-disease population. Weight loss and gain were recorded in 44.4% and 5% of patients, respectively. Low muscle mass was more frequently associated with BMI < 25 kg/m2 (p < 0.000001). Overall survival was positively affected by pre-disease (p = 0.036) and pre-surgery (p = 0.017) BMI > 25 kg/m2, and, even more, in case of BMI > 25 kg/m2 and increasing weight (p = 0.012). Long-term outcome was negatively influenced by low muscle mass (p = 0.042) and weight loss (p = 0.0052) as well as age (p = 0.017), ASA categories (p = 0.025), extent of resection (p = 0.0001), pleural invasion (p = 0.0012) and higher pathologic stage (p < 0.0001). Three stepwise multivariable models confirmed the independent favorable prognostic value of higher pre-disease (RR 0.66[0.49–0.89], p = 0.006) and pre-surgery BMI (RR 0.72[0.54–0.98], p = 0.034), and the absence of low muscle mass (RR 0.56[0.37–0.87], p = 0.0091). Conclusions: Body reserves assessed by simple clinical markers impact survival of surgically treated NSCLC. Strategies improving body fat and muscular mass before surgery should be considered. [ABSTRACT FROM AUTHOR]