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.

Genomic and Immunophenotypic Landscape of Acquired Resistance to PD-(L)1 Blockade in Non-Small-Cell Lung Cancer.

PURPOSE: Although immune checkpoint inhibitors (ICI) have extended survival in patients with non-small-cell lung cancer (NSCLC), acquired resistance (AR) to ICI frequently develops after an initial benefit. However, the mechanisms of AR to ICI in NSCLC are largely unknown. METHODS: Comprehensive tumor genomic profiling, machine learning-based assessment of tumor-infiltrating lymphocytes, multiplexed immunofluorescence, and/or HLA-I immunohistochemistry (IHC) were performed on matched pre- and post-ICI tumor biopsies from patients with NSCLC treated with ICI at the Dana-Farber Cancer Institute who developed AR to ICI. Two additional cohorts of patients with intervening chemotherapy or targeted therapies between biopsies were included as controls. RESULTS: We performed comprehensive genomic profiling and immunophenotypic characterization on samples from 82 patients with NSCLC and matched pre- and post-ICI biopsies and compared findings with a control cohort of patients with non-ICI intervening therapies between biopsies (chemotherapy, N = 32; targeted therapies, N = 89; both, N = 17). Putative resistance mutations were identified in 27.8% of immunotherapy-treated cases and included acquired loss-of-function mutations in STK11, B2M, APC, MTOR, KEAP1, and JAK1/2; these acquired alterations were not observed in the control groups. Immunophenotyping of matched pre- and post-ICI samples demonstrated significant decreases in intratumoral lymphocytes, CD3e+ and CD8a+ T cells, and PD-L1-PD1 engagement, as well as increased distance between tumor cells and CD8+PD-1+ T cells. There was a significant decrease in HLA class I expression in the immunotherapy cohort at the time of AR compared with the chemotherapy (P = .005) and the targeted therapy (P = .01) cohorts. CONCLUSION: These findings highlight the genomic and immunophenotypic heterogeneity of ICI resistance in NSCLC, which will need to be considered when developing novel therapeutic strategies aimed at overcoming resistance.

Magnetically Inserted Neural Electrodes: Tissue Response and Functional Lifetime.

Neural recording and stimulation have great clinical potential. Long-term neural recording remains a challenge, however, as implantable electrodes eventually fail due to the adverse effects of the host tissue response to the indwelling implant. Astrocytes and microglia attempt to engulf the electrode, increasing the electrical impedance between the electrode and neurons, and possibly pushing neurons away from the recording site. Faster insertion speed, finer tip geometry, smaller size, and lower material stiffness all seem to decrease damage caused by insertion and reduce the intensity of the tissue response. However, electrodes that are too small result in buckling, making insertion impossible. In this paper, we assess the viability of high-speed (27.8 m/s) deployment of 25 µm, ferromagnetic microelectrodes into rat brain. To characterize functionality of magnetically inserted electrodes, 4 Long-Evans rats were implanted for 31 days with impedance measurements and neural recordings taken daily. Performance was compared to 150 µm diameter PlasticsOne electrodes since 25 µm electrodes buckled during "slow speed" insertion. Platinum-iron magnetically inserted electrodes resolved single unit activity throughout the duration of the study in one rat, and saw no significant change (p=0.970) in impedance (4.54% increase) from day 0 (Z0 ≈ 144 kΩ,Z31 ≈ 150 kΩ). These findings provide a proof-of-concept for magnetic insertion as a viable insertion method that enables nonbuckling implantation of small (25 µm) microelectrodes, with potential for neural recording applications.