CD4+ T cells play a central role in immune protection. Tumors might impair CD4+ T cell immune function, and this might contribute to tumor escape, a relevant finding in pancreatic cancer (PC). Aims were to: 1. compare the effects of PC and other gastrointestinal cancer (GIC) cells on human CD4+ T cells proliferation, migration and Th1 differentiation; 2. analyse whether cancer cells modify the expansion of CD4+ cell memory (CD45RO), naïve (CD45RA), activated (CD69) and regulatory (CD25) subsets. Methods: CD4+ T lymphocytes were purified from blood donors’ buffy coats (n=29) (RosetteSep kit, StemCell Technologies). CD4+ T cells were cultured for 4 days in control medium or in pancreatic (BxPC3, Capan1, MiaPaCa 2), colorectal (HT29), gastric (AGS) or hepatocellular (HepG2) cancer cell conditioned media (CM). Migration was assessed using a transwell system in the presence or absence of the chemoattractant hSDFα; the number of migrating cells was estimated by a luminescent cell viability assay (CellTiter-Glo®, Invitrogen). Cell proliferation, in the presence or absence of allogenic PBMC, was evaluated after 72 hrs (3H-Thymidine incorporation). IFNγ (ELISA) was measured in the supernatants of control and cancer conditioned CD4+ T cells after 4 culture days. CD45RA, CD45RO, CD69 and CD25 membrane expression was FACS analysed in control and conditioned CD4+ T cells before and after 4 culture days. Results: Both in the presence (χ2 =110, p<0.001) and absence (χ2 =26.4, p<0.001) of PBMC, only PC cell CM significantly lowered CD4+ T cells proliferation with respect to control or other GIC. In the absence of hSDFα, a higher number of PC and other GIC conditioned CD4+ T cells transmigrate with respect to control (p<0.001); in the presence of hSDFα only PC cell CM significantly reduced CD4+ T cell migration with respect to control (χ2 =40.3, p<0.001). All PC CM significantly induced CD4+ T cell production of IFNγ (p<0.01 for BxPc3, p<0.05 for Capan1 and MiaPaCa2). Control or other GIC CM did not affect IFNγ production (p:ns). Control or tumor CM did not modify CD45RA, CD45RO or CD25 subsets. CD69 positive cells were significantly expanded by PC cell CM (χ2 =15, p<0.001 for BxPc3, χ2=16, p<0.001 for Capan1, χ2 =10, p<0.01 for MiaPaCa2) but not by other GIC cell CM (χ2 =0.4, p:ns). Conclusions: PC cells, differently from other GIC cells, inhibit CD4+ T cell proliferation, migration under hSDFα chemotaxis and induce both CD4+ T cells activation and differentiation into the Th1 phenotype. Overall these “in vitro” findings support the hypothesis that PC might evade immunesurveillance by altering CD4+ T lymphocytes.