Abstract 4103: Blockade of intrinsic PD-1 promotes human colon cancer cells survival, chemo resistance and in vivo tumor growth of human colon cancer cells

Abstract

Abstract A considerable proportion of colorectal cancer patients develops local recurrence and distant metastasis within 5 years after surgical treatment. The anti-PD-1, Nivolumab, is indicated for treatment of patients with metastatic colorectal cancer carrying DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) whose disease has progressed on fluoropyrimidine, oxaliplatin, and irinotecan. Thus only a minority of patients with CRC will benefit from the immunotherapy. Beyond immune cell expression, recent evidence demonstrates that PD-1 is expressed on human cancer cells, such as melanoma and NSCLC cells. It is possible to speculate that colon cancer immune resistance could partially reside on intrinsic colon cancer cells PD-1 overexpression. PD-1 expression was evaluated through RT-PCR and flow cytometry in human colon cancer cell lines (HT29, HCT116, SW620, Colo205, LOVO). PD-1 was robustly expressed in HT29 (74,4%), in HCT116 (57,5%) and in SW620 (62,9%) while the ligand PD-L1 was weakly expressed in these cell lines. Recombinant PD-L1 fusion protein significantly decreased HT29 and HCT116 proliferation, while Nivolumab protects the cells by PD-L1 effect. To investigate on the effect of PD-1 on chemo sensitivity, cytotoxicity assays were conducted with Oxaplatinum (OXAL) or 5-Fluoruracil (5-FU) in the presence of Nivolumab. Unexpectedly, Nivolumab significantly protected cancer cells from OXAL and 5-FU (HT29 cells were 2.02- and 1.77-fold more resistant to 5FU and OXAL in the presence of Nivolumab and HCT116 were 1,7- and 2,1-fold more resistant to 5FU and OXAL in the presence of Nivolumab). Moreover, Nivolumab protected HT29 cells from apoptosis 5-FU-OXAL induced at 72 hrs. In vivo, Nivolumab accelerated the growth of subcutaneous HT29 tumor growth and reduced the efficacy of chemotherapy. Mechanistically, preliminary results demonstrated that Nivolumab increased the mTOR target p4EBP1, pErk and p38 signaling. Taken together, these results demonstrate that, while intrinsic PD-1 axis activation decreases human colon cancer cell proliferation, Nivolumab protects the human colon cancer cells PD-1 overexpressing. These effects need to be considered in the evaluation of immunotherapy efficacy in colon cancer. Citation Format: Caterina Ieranò, Crescenzo D'Alterio, Maria Napolitano, Luigi Portella, Giuseppina Rea, Gelsomina Monaco, Piera Maiolino, Antonio Luciano, Antonio Barbieri, Giuseppe Palma, Claudio Arra, Roberto Pacelli, Stefania Scala. Blockade of intrinsic PD-1 promotes human colon cancer cells survival, chemo resistance and in vivo tumor growth of human colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4103.