Investigating of Immunotherapy and Combination Treatments in Ex-Vivo Culture Model of NSCLC

Abstract

Background: NSCLC induces pro-tumorigenic immunosuppressive changes to evade the immune system. Response of tumors to therapy, including to immunotherapy, depends on interactions of epithelial tumor cells and the microenvironment. Ex vivo culture (EVOC) models directly established from fresh NSCLC tumor tissues can be used as a complete model that resembles real tumor and its microenvironment. Little is known about the impact of drugs such as chemotherapy, radiotherapy or targeted agents on the expression and activity of the PD1-PDL1 signaling in human cancers. Combining such treatments with immunotherapy seems to be a promising approach that is actively investigated. We are using an EVOC model to study the impact of anti-PDL1 agents in NSCLC, alone or in combination with other therapeutics (chemotherapy or radiotherapy). Results: Our results indicate our EVOC model applicability as modeling immunotherapy effects in cancer. Specifically, tumor and stromal cells are maintained with a stable structure over a time window of several days and cell death is seen in response to cytotoxic drugs. Importantly, PDL1 is dramatically induced in response to inflammation signals (e.g. IFNg), PDL1 is reduced in response to steroids and variability in PDL-1 expression is seen between EVOCs from different NSCLC patients. Conclusions: NSCLC EVOC is a promising model for elucidation of immunotherapy and other drugs impact on real human cancer with its native microenvironment and immune cells.

MACC1 regulates PDL1 expression and tumor immunity through the c‐Met/AKT/mTOR pathway in gastric cancer cells

“…In treating many types of cancer, immunotherapy targeting PD-1/PDL1 is a breakthrough and has great promise in cancer treatment 5 In 2015, The US FDA approved anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab for advanced non-small cell lung cancer treatment, which achieved a good therapeutic effect. 6,7 Both antigen-presenting cells and cancer cells can express PDL1, and PDL1 expression of numerous tumor is associated with immune evasion. 8 Zou et al noted that overexpression of PDL1 may be one mechanism by which tumor cells escape the PD-1/PDL1 immune inhibitory pathway.…”

“…In the regulation of immune responses, many studies have inferred that the programmed cell death‐1 (PD‐1)/programmed cell death ligand 1 (PDL1) pathway has important roles. In treating many types of cancer, immunotherapy targeting PD‐1/PDL1 is a breakthrough and has great promise in cancer treatment In 2015, The US FDA approved anti‐PD‐1 monoclonal antibodies nivolumab and pembrolizumab for advanced non‐small cell lung cancer treatment, which achieved a good therapeutic effect . Both antigen‐presenting cells and cancer cells can express PDL1, and PDL1 expression of numerous tumor is associated with immune evasion .…”