Nonsignaling extracellular spacer regulates tumor antigen selectivity of CAR T cells.

Advancing chimeric antigen receptor (CAR)-engineered T cells for the treatment of solid tumors is a major focus in the field of cellular immunotherapy. Several hurdles have hindered similar CAR T cell clinical responses in solid tumors as seen in hematological malignancies. These challenges include on-target off-tumor toxicities, which have inspired efforts to optimize CARs for improved tumor antigen selectivity and overall safety.

Targeting SCD triggers lipotoxicity of cancer cells and enhances anti-tumor immunity in breast cancer brain metastasis mouse models.

Breast cancer brain metastases (BCBM) are a significant cause of mortality and are incurable. Thus, identifying BCBM targets that reduce morbidity and mortality is critical. BCBM upregulate Stearoyl-CoA Desaturase (SCD), an enzyme that catalyzes the synthesis of monounsaturated fatty acids, suggesting a potential metabolic vulnerability of BCBM.

Metabolic programs of T cell tissue residency empower tumour immunity.

Tissue resident memory CD8 T (T) cells offer rapid and long-term protection at sites of reinfection. Tumour-infiltrating lymphocytes with characteristics of T cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses. Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours.

Decoding the crosstalk between mevalonate metabolism and T cell function.

The mevalonate pathway is an essential metabolic pathway in T cells regulating development, proliferation, survival, differentiation, and effector functions. The mevalonate pathway is a complex, branched pathway composed of many enzymes that ultimately generate cholesterol and nonsterol isoprenoids. T cells must tightly control metabolic flux through the branches of the mevalonate pathway to ensure sufficient isoprenoids and cholesterol are available to meet cellular demands.

Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity.

Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its effectiveness in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate and pancreas cancer, including those targeting prostate stem cell antigen (PSCA), are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human PSCA knockin (hPSCA-KI) immunocompetent mouse model, we evaluated the safety and therapeutic efficacy of PSCA-CAR T cells.

Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer.

Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with "on-target off-tumor" activity.