Although not traditional rivals, tensions between the two sides intensified after five years of facing each other in non-League and victory on Saturday secured Luton a league double over Cambridge.
Richard Money, the visitors' manager and former Luton tactician, resisted the urge to make wholesale changes ahead of Wednesday's Old Trafford clash, though his side struggled before the break.
Third-placed Wycombe Wanderers dropped points for the third successive match as they were held to a goalless draw at home to Portsmouth, while Southend United remain on Luton's coattails thanks to Shaquile Coulthirst's late penalty in a 1-0 win over struggling York City.
Also at the wrong end of the table, rock-bottom Hartlepool United gave their survival chances a boost as they beat Plymouth Argyle 3-2, but Mansfield Town were unable to capitalise on York's defeat, as they lost 2-1 at Carlisle United to stay in the bottom two.
Northampton Town – who had Ryan Cresswell dismissed in the 38th minute – became the division's top scorers with a 5-1 triumph at Accrington Stanley.
