T cell egress via lymphatic vessels is tuned by antigen encounter and limits tumor control.

Antigen-specific CD8+ T cell accumulation in tumors is a prerequisite for effective immunotherapy, and yet the mechanisms of lymphocyte transit are not well defined. Here we show that tumor-associated lymphatic vessels control T cell exit from tumors via the chemokine CXCL12, and intratumoral antigen encounter tunes CXCR4 expression by effector CD8+ T cells. Only high-affinity antigen downregulates CXCR4 and upregulates the CXCL12 decoy receptor, ACKR3, thereby reducing CXCL12 sensitivity and promoting T cell retention. A diverse repertoire of functional tumor-specific CD8+ T cells, therefore, exit the tumor, which limits the pool of CD8+ T cells available to exert tumor control. CXCR4 inhibition or loss of lymphatic-specific CXCL12 boosts T cell retention and enhances tumor control. These data indicate that strategies to limit T cell egress might be an approach to boost the quantity and quality of intratumoral T cells and thereby response to immunotherapy.

An activation to memory differentiation trajectory of tumor-infiltrating lymphocytes informs metastatic melanoma outcomes.

There is a need for better classification and understanding of tumor-infiltrating lymphocytes (TILs). Here, we applied advanced functional genomics to interrogate 9,000 human tumors and multiple single-cell sequencing sets using benchmarked T cell states, comprehensive T cell differentiation trajectories, human and mouse vaccine responses, and other human TILs. Compared with other T cell states, enrichment of T memory/resident memory programs was observed across solid tumors. Trajectory analysis of single-cell melanoma CD8+ TILs also identified a high fraction of memory/resident memory-scoring TILs in anti-PD-1 responders, which expanded post therapy. In contrast, TILs scoring highly for early T cell activation, but not exhaustion, associated with non-response. Late/persistent, but not early activation signatures, prognosticate melanoma survival, and co-express with dendritic cell and IFN-γ response programs. These data identify an activation-like state associated to poor response and suggest successful memory conversion, above resuscitation of exhaustion, is an under-appreciated aspect of successful anti-tumoral immunity.

Safety and efficacy of ultrasonography as an adjunct to fluoroscopy for renal access in percutaneous nephrolithotomy (PCNL).

OBJECTIVE: • To evaluate the safety and efficacy of ultrasonography (US)-guided renal access in percutaneous nephrolithotomy (PCNL), as compared with conventional fluoroscopy-guided renal access in a prospective randomized trial. PATIENTS AND METHODS: • From January 2008 to October 2009, 224 patients with renal calculi undergoing PCNL were randomized into two groups. • Group 1 (112 patients) underwent PCNL using only fluoroscopy-guided renal access; while in group 2 (112 patients), US guidance for puncture was used in addition to fluoroscopy. • The inclusion criteria were: normal renal functions, American Society of Anesthesiology scores 1 or 2, absence of congenital abnormalities, aged 15-70 years, and anticipated single-tract procedure. The patients in both groups were matched for age, sex, and stone characteristics. • The Student t-test was used for statistical analysis with an allowable error of 5%. RESULTS: • The mean time to successful puncture was 3.2 min and 1.8 min in group 1 and group 2, respectively (P < 0.01). • The mean duration of radiation exposure to successful puncture was 28.6 s in group 1 and 14.4 s in group 2 (P < 0.01). • The mean numbers of attempts for successful puncture in the desired calyx was 3.3 in group 1 as compared with 1.5 in group 2 (P < 0.01). • The meantime taken for tract formation in group 1 was 7.4 min with radiation exposure of 82 s, while in group 2 it took 4.8 min with radiation exposure of 58 s (P < 0.01). • Successful access was achieved in all patients. All patients were stone-free at the end of the operation. The hospital stay (2-3 days) was same in both groups. There was no incidence of significant bleeding requiring transfusion during or after surgery. All the patients were followed-up for a ≥ 6 months. CONCLUSION: • US-guided puncture in PCNL helps in increasing accuracy of puncture and decreasing radiation exposure for the surgical team and the patients.