Targeting the PD-1/PD-L1 axis for the treatment of non-small-cell lung cancer.

Lung cancer is the leading cause of cancer-specific death among Canadians, with non-small-cell lung cancer (nsclc) being the most common histologic variant. Despite advances in the understanding of the molecular biology of nsclc, the survival rate for this malignancy is still poor. It is now understood that, to evade detection and immune clearance, nsclc tumours overexpress the immunosuppressive checkpoint protein programmed death ligand 1 (PD-L1). Inhibiting the PD-1/PD-L1 axis with monoclonal antibodies has significantly changed the treatment landscape in nsclc during the last 5 years. Despite evidence of clinical response in some patients, only approximately 20% of patients obtain any durable benefit, and many of the patients who do respond ultimately relapse with drug-resistant disease. The identification of patients who are most likely to benefit from such therapy is therefore important. In the present review, we cover the basics of the PD-1/PD-L1 axis and its clinical significance in nsclc, biomarkers that are predictive of treatment response, relevant clinical trials of PD-1/PD-L1 blockade completed to date, and proposed mechanisms of acquired therapeutic resistance.

Properties of the depolarizing synaptic potential evoked by peripheral illumination in cones of the turtle retina.

1. Intracellular recordings of cone and horizontal cell responses to circles or annuli of light were made with the purpose of determining the properties of and the mechanisms underlying the horizontal-cell-mediated depolarization of cones which is evoked by surround illumination.2. A comparison of the responses of a cone and a near-by horizontal cell to a peripheral stimulus revealed a striking similarity in their time courses and amplitudes, indicating that a correlation exists between the depolarizing synaptic potential in the cone and the response of the horizontal cell.3. The depolarizing synaptic potential in cones was separated from the direct response of the cell to light by illuminating the periphery with an annulus during steady, bright illumination of the central cone. The synaptic potentials were graded with the intensity or area of peripheral illumination. In some cones a spike-like depolarization, which overshot the dark resting potential, occurred with bright illumination of the periphery.4. The effects of extrinsic current on the synaptic potential demonstrated that this response was generated by a change in membrane conductance consisting of two separate components with different time-dependences and reversal levels. The slower of the two components, which often outlasts the stimulus, represents an increase in membrane conductance.5. The progressive decline in the amplitude of the responses of horizontal cells under a large spot from centre to periphery was found to result in a diminished feed-back effect in cones near the edge of the spot. This leads to a Mach-band effect during the plateau phase of cone responses, suggesting that one function of the feed-back might be to enhance contrast discrimination.

Receptive fields of cones in the retina of the turtle.

1. Intracellular recordings have been made of the responses to light of single cones in the retina of the turtle. The shape of the hyperpolarizing response to a flash depends on the pattern of retinal illumination as well as the stimulus intensity.2. Although changes in the stimulus pattern can produce changes in the effective stimulus intensity, the responses to certain patterns cannot be matched by any adjustment of stimulus intensity.3. The initial portion of responses to large or small stimulating spots is proportional to light intensity; this allows comparison of responses when the amount of light on a cone is kept constant but the light on surrounding cones is changed. For equal light intensity on the cone, the response to a spot 2 or 4 mu in radius is smaller than that to a spot 70 mu in radius.4. Responses to spots 70 and 600 mu in radius coincide over their rising phases and peaks without any adjustment of stimulus intensity. The responses to the larger spot, however, contain a delayed depolarization not present with the smaller spot.5. During steady illumination of a cone with a small central spot, the response to transient illumination superimposed on the same area is greatly reduced. Illumination of cones in the near surround, however, produces a hyperpolarizing response, and illumination of cones in the more distant surround generates a delayed depolarization.6. The results described above suggested that synaptic signals might impinge on cones. This possibility was tested by electrically polarizing one retinal cell while recording from another.7. Currents passed through a cone within 40 mu of another cone can change the membrane potential of the latter. Not all cones within this distance show the interaction, however, and it has never been detected at distances greater than 50 mu.8. Hyperpolarization of a horizontal cell with applied current can produce a depolarization of a cone in the vicinity. During this depolarization, the response of the cone to a flash is reduced in size and altered in shape.9. It is concluded that the response of a cone to light may be modified by synaptic mechanisms which are activated by peripheral illumination.