Blockade of intrinsic PD-1 promotes survival, chemo resistance and tumor growth in human colon cancer

Human colon cancer cells HT29, HCT116, LoVo robustly expressed PD-1. PD-1 signaling significantly decreased proliferation and promoted apoptosis in PD1+human colon cancer cells. The human anti-PD-1, Nivolumab (NIVO) ptomoted proliferation through pERK/pAKT signaling, reduced apoptosis and protected PD-1+ cells from Chemo/Radiotherapy (CRT). In vivo, NIVO promoted HT29 tumor growth reducing Oxaliplatin (OX) efficacy. As opposite to colon cancer cells, PD-1 signaling protects melanoma cells, thus NIVO treated human colon versus melanoma cancer cells, PES43 were evaluated for RNAseq. Among the commonly affected genes, opposite regulation was revealed between HT29 and HCT116 colon versus PES43 melanoma cells. BATF2, DRAM1, FXYD3, IFIT3, MT-TN, TNFRSF11A were upregulated in PES43 and downregulated in HT29 and HCT116 while CLK1, DCAF13, DNAJC2, MTHFD1L, PRPF3, PSMD7, SCFD1 were downregulated in PES43 and upregulated in HT29 and HCT116. DEGs were significantly enriched in the functional categories of the interferon pathway, innate immune, cytokine-mediated signaling pathway, neutrophil activation, immune effector process, granulocyte activation and cellular nitrogen compound metabolic process. Moreover, intrinsic PD-1 was expressed in 11/48 (22.9%) primary colorectal cancer and associated with tumor dimension (pT). Thus, PD-1 inhibition through NIVO protects human colon cancer cells and activate tumor survival pathways mRNA profile Nivolumab (NIVO), soluble PD-L1 (sPDL-1) and NIVO+sPDL-1-treated human colorectal cancer cells HCT116 and HT29 and human melanoma cells PES43 for 6h and 24h