Immunometabolism (Cobham)
January 2025
The approval of chimeric antigen receptor (CAR) T cell therapies for the treatment of hematological cancers has marked a new era in cancer care, with seven products being FDA approved since 2017. However, challenges remain, and while profound effects are observed initially in myeloma, the majority of patients relapse, which is concomitant with poor CAR T cell persistence. Similarly, the efficacy of CAR T cell therapy is limited in solid tumors, largely due to tumor antigen heterogeneity, immune evasion mechanisms, and poor infiltration and persistence.
View Article and Find Full Text PDFIn this issue of Cancer Cell, Qiu et al. use single-cell metabolic analysis to identify reduced mannose metabolism as a previously unknown feature of exhausted T cells. This metabolic pathway can be targeted to enhance memory and persistence of adoptively transferred T cells, resulting in improved anti-tumor efficacy.
View Article and Find Full Text PDFMacrophages represent a key component of the tumor microenvironment (TME) and are largely associated with poor prognosis. Therapeutic targeting of macrophages has historically focused on inhibiting their recruitment or reprogramming their phenotype from a protumor (M2-like) to an antitumor (M1-like) one. Unfortunately, this approach has not provided clinical breakthroughs that have changed practice.
View Article and Find Full Text PDFThere is significant clinical interest in targeting adenosine-mediated immunosuppression, with several small molecule inhibitors having been developed for targeting the AR receptor. Understanding of the mechanism by which AR is regulated has been hindered by difficulty in identifying the cell types that express AR due to a lack of robust antibodies for these receptors. To overcome this limitation, here an AR eGFP reporter mouse is developed, enabling the expression of AR during ongoing anti-tumor immune responses to be assessed.
View Article and Find Full Text PDFCXCL9 expression is a strong predictor of response to immune checkpoint blockade therapy. Accordingly, we sought to develop therapeutic strategies to enhance the expression of CXCL9 and augment antitumor immunity. To perform whole-genome CRISPR-Cas9 screening for regulators of CXCL9 expression, a CXCL9-GFP reporter line is generated using a CRISPR knockin strategy.
View Article and Find Full Text PDFNovel therapeutic strategies that can effectively combine with immunotherapies are needed in the treatment of triple-negative breast cancer (TNBC). We demonstrate that combined PARP and WEE1 inhibition are synergistic in controlling tumour growth in BRCA1/2 wild-type TNBC preclinical models. The PARP inhibitor (PARPi) olaparib combined with the WEE1 inhibitor (WEE1i) adavosertib triggered increases in anti-tumour immune responses, including STING pathway activation.
View Article and Find Full Text PDFBackground: Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors have poor efficacy in patients with trastuzumab-resistant advanced HER2-positive breast cancer. Tucatinib is a potent, selective anti-HER2 tyrosine kinase inhibitor with proven clinical benefit in the advanced setting in patients with trastuzumab resistance. We investigated if tucatinib can alter the tumor microenvironment and if this could be harnessed for therapeutic efficacy.
View Article and Find Full Text PDFPatients who receive chimeric antigen receptor (CAR)-T cells that are enriched in memory T cells exhibit better disease control as a result of increased expansion and persistence of the CAR-T cells. Human memory T cells include stem-like CD8 memory T cell progenitors that can become either functional stem-like T (T) cells or dysfunctional T progenitor exhausted (T) cells. To that end, we demonstrated that T cells were less abundant in infused CAR-T cell products in a phase 1 clinical trial testing Lewis Y-CAR-T cells (NCT03851146), and the infused CAR-T cells displayed poor persistence in patients.
View Article and Find Full Text PDFCD8 tumor-infiltrating lymphocytes with a tissue-resident memory T (T) cell phenotype are associated with favorable prognosis in patients with triple-negative breast cancer (TNBC). However, the relative contribution of CD8 T cells to anti-tumor immunity and immune checkpoint blockade efficacy in breast cancer remains unknown. Here, we show that intratumoral CD8 T cells in murine mammary tumors transcriptionally resemble those from TNBC patients.
View Article and Find Full Text PDFPurpose: Tumor cells thrive by adapting to the signals in their microenvironment. To adapt, cancer cells activate signaling and transcriptional programs and migrate to establish micro-niches, in response to signals from neighboring cells and non-cellular stromal factors. Understanding how the tumor microenvironment evolves during disease progression is crucial to deciphering the mechanisms underlying the functional behavior of cancer cells.
View Article and Find Full Text PDFBreast cancer (BCa) incidence increases following aberrant hormone exposure, which has been linked to direct effects on estrogen receptor (ER) mammary epithelium. While estrogen exposure during mammary involution has been shown to drive tumour growth via neutrophils, the potential for the ER + immune microenvironment to mediate part (in addition to mammary epithelial cells) of hormonally controlled BCa risk during normal development has not been assessed. We collected mammary tissue, lymph nodes and blood from tumour naïve mice treated with, oophorectomy, estrogen (17β estradiol) or Fulvestrant.
View Article and Find Full Text PDFPatients with refractory relapsed multiple myeloma respond to combination treatment with elotuzumab and lenalidomide. The mechanisms underlying this observation are not fully understood. Furthermore, biomarkers predictive of response have not been identified to date.
View Article and Find Full Text PDFNatural Killer T (NKT) cells and Mucosal-Associated Invariant T (MAIT) cells are innate-like T cells that express semi-invariant αβ T cell receptors (TCRs) through which they recognise CD1d and MR1 molecules, respectively, in complex with specific ligands. These cells play important roles in health and disease in many organs, but their precise intra-organ location is not well established. Here, using CD1d and MR1 tetramer staining techniques, we describe the precise location of NKT and MAIT cells in lymphoid and peripheral organs.
View Article and Find Full Text PDFAdoptive cell therapy with chimeric antigen receptor (CAR) T cells has revolutionized the treatment of certain B cell malignancies but has been in ineffective against solid tumors. Recent studies have highlighted the potential of targeting negative regulators of T cell signaling to enhance the efficacy and extend the utility of CAR T cells to solid tumors. Autoimmunity-linked protein tyrosine phosphatase N22 (PTPN22) has been proposed as a target for cancer immunotherapy.
View Article and Find Full Text PDFCancer immunotherapy utilizing checkpoint blockade antibodies or adoptive cellular therapy (ACT) with tumor-specific T cells has led to unprecedented clinical responses in patients with cancer and has been considered one of the most significant breakthroughs in cancer treatment in the past decade. Nevertheless, many cancers remain refractory to these therapies due to the presence of an immunosuppressive tumor microenvironment. This has led to the innovative idea of combining ACT with checkpoint inhibition.
View Article and Find Full Text PDFUnlabelled: Immunotherapies aimed at alleviating the inhibitory constraints on T cells have revolutionized cancer management. To date, these have focused on the blockade of cell-surface checkpoints such as PD-1. Herein we identify protein tyrosine phosphatase 1B (PTP1B) as an intracellular checkpoint that is upregulated in T cells in tumors.
View Article and Find Full Text PDFIn this issue of Cancer Cell, Xue et al. demonstrate that adoptive transfer of tumor-specific Th9 cells can eradicate established tumors containing antigen-loss-variant cells (ALVs) through both direct killing and bystander effects mediated by intratumoral accumulation of extracellular ATP (eATP) that promotes monocyte infiltration and stimulation of IFNα/β production.
View Article and Find Full Text PDFSarcomas are a diverse group of bone and soft tissue tumors that account for over 10% of childhood cancers. Outcomes are particularly poor for children with refractory, relapsed, or metastatic disease. Chimeric antigen receptor T (CAR T) cells are an exciting form of adoptive cell therapy that potentially offers new hope for these children.
View Article and Find Full Text PDFPurpose: In this article, we describe a combination chimeric antigen receptor (CAR) T-cell therapy that eradicated the majority of tumors in two immunocompetent murine pancreatic cancer models and a human pancreatic cancer xenograft model.
Experimental Design: We used a dual-specific murine CAR T cell that expresses a CAR against the Her2 tumor antigen, and a T-cell receptor (TCR) specific for gp100. As gp100 is also known as pMEL, the dual-specific CAR T cells are thus denoted as CARaMEL cells.
The function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear. Here we show that MAIT cell-deficient mice have enhanced NK cell-dependent control of metastatic B16F10 tumor growth relative to control mice. Analyses of this interplay in human tumor samples reveal that high expression of a MAIT cell gene signature negatively impacts the prognostic significance of NK cells.
View Article and Find Full Text PDFTher Adv Vaccines Immunother
May 2021
Tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T-cell therapies have demonstrated promising, though limited, efficacy against melanoma. We designed a model system to explore the efficacy of dual specific T cells derived from melanoma patient TILs by transduction with a Her2-specific CAR. Metastatic melanoma cells in our biobank constitutively expressed Her2 antigen.
View Article and Find Full Text PDFAdenosine is an immunosuppressive factor that limits anti-tumor immunity through the suppression of multiple immune subsets including T cells via activation of the adenosine A receptor (AR). Using both murine and human chimeric antigen receptor (CAR) T cells, here we show that targeting AR with a clinically relevant CRISPR/Cas9 strategy significantly enhances their in vivo efficacy, leading to improved survival of mice. Effects evoked by CRISPR/Cas9 mediated gene deletion of AR are superior to shRNA mediated knockdown or pharmacological blockade of AR.
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