TCR-engineered T cell therapy in solid tumors: State of the art and perspectives.

T cell engineering has changed the landscape of cancer immunotherapy. Chimeric antigen receptor T cells have demonstrated a remarkable efficacy in the treatment of B cell malignancies in hematology. However, their clinical impact on solid tumors has been modest so far. T cells expressing an engineered T cell receptor (TCR-T cells) represent a promising therapeutic alternative. The target repertoire is not limited to membrane proteins, and intrinsic features of TCRs such as high antigen sensitivity and near-to-physiological signaling may improve tumor cell detection and killing while improving T cell persistence. In this review, we present the clinical results obtained with TCR-T cells targeting different tumor antigen families. We detail the different methods that have been developed to identify and optimize a TCR candidate. We also discuss the challenges of TCR-T cell therapies, including toxicity assessment and resistance mechanisms. Last, we share some perspectives and highlight future directions in the field.

[T cell-based immunotherapies in solid tumors]. / Approches d'immunothérapie cellulaire T dans les tumeurs solides.

In solid tumors, adoptive T cell therapies based on ex vivo amplification of antitumor T cell are represented by three main complementary approaches : (i) tumor infiltrating lymphocytes (TILs) which are amplified in vitro before reinjection to the patient, (ii) chimeric antigen receptor (CAR) engineered T cells and (iii) T cell receptor (TCR) engineered T cells. Despite encouraging results, some obstacles remain, such as optimal target selection and tumor microenvironment. In this Review, we discuss pros and cons of these different therapeutic strategies that may open new perspectives in the treatment of solid tumors.

Increasing G9a automethylation sensitizes B acute lymphoblastic leukemia cells to glucocorticoid-induced death.

Synthetic glucocorticoids (GCs) are used to treat lymphoid cancers, but many patients develop resistance to treatment, especially to GC. By identifying genes that influence sensitivity to GC-induced cell death, we found that histone methyltransferases G9a and G9a-like protein (GLP), two glucocorticoid receptor (GR) coactivators, are required for GC-induced cell death in acute lymphoblastic leukemia (B-ALL) cell line Nalm6. We previously established in a few selected genes that automethylated G9a and GLP recruit heterochromatin protein 1γ (HP1γ) as another required coactivator. Here, we used a genome-wide analysis to show that HP1γ is selectively required for GC-regulated expression of the great majority of GR target genes that require G9a and GLP. To further address the importance of G9a and GLP methylation in this process and in cell physiology, we found that JIB-04, a selective JmjC family lysine demethylase inhibitor, increased G9a methylation and thereby increased G9a binding to HP1γ. This led to increased expression of GR target genes regulated by G9a, GLP and HP1γ and enhanced Nalm6 cell death. Finally, the KDM4 lysine demethylase subfamily demethylates G9a in vitro, in contrast to other KDM enzymes tested. Thus, inhibiting G9a/GLP demethylation potentially represents a novel method to restore sensitivity of treatment-resistant B-ALL tumors to GC-induced cell death.