Exosomal PD-L1 promotes tumor growth through immune escape in non-small cell lung cancer

Abstract

Programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) pathway blockade is a promising new cancer therapy. Although PD-1/PD-L1 treatment has yielded clinical benefits in several types of cancer, further studies are required to clarify predictive biomarkers for drug efficacy and to understand the fundamental mechanism of PD-1/PD-L1 interaction between host and tumor cells. Here, we show that exosomes derived from lung cancer cells express PD-L1 and play a role in immune escape by reducing T-cell activity and promoting tumor growth. The abundance of PD-L1 on exosomes represented the quantity of PD-L1 expression on cell surfaces. Exosomes containing PD-L1 inhibited interferon-gamma (IFN-γ) secretion by Jurkat T cells. IFN-γ secretion was restored by PD-L1 knockout or masking on the exosomes. Both forced expression of PD-L1 on cells without PD-L1 and treatment with exosomes containing PD-L1 enhanced tumor growth in vivo. PD-L1 was present on exosomes isolated from the plasma of patients with non-small cell lung cancer, and its abundance in exosomes was correlated with PD-L1 positivity in tumor tissues. Exosomes can impair immune functions by reducing cytokine production and inducing apoptosis in CD8+ T cells. Our findings indicate that tumor-derived exosomes expressing PD-L1 may be an important mediator of tumor immune escape.

Tumor secreted extracellular vesicles regulate T-cell costimulation and can be manipulated to induce tumor specific T-cell responses

“…The WT TEVs are considered as immunosuppressive in general (Iero et al, 2008;Kurywchak et al, 2018). However, recent findings identified the immunosuppressive factors in those TEVs and showed that blocking them can alleviate the immunosuppression (Chen et al, 2018;Kim et al, 2019;Poggio et al, 2019). Further, adding immunostimulatory factors into the TEVs can even enhance their ability to initiate immune responses (Diamond et al, 2018).…”

Extracellular Vesicles and Tumor-Immune Escape: Biological Functions and Clinical Perspectives

“…This discrepancy can occur due to temporal and spatial tumor heterogeneity and to the difficulty of performing biopsies at multiple time points. In this perspective, the use of liquid biopsy is strongly encouraged since it can be easily repeated over time and can reflect the overall state of a tumor, overcoming the problems associated with heterogeneity [150].…”

Extracellular Vesicles in Non-Small-Cell Lung Cancer: Functional Role and Involvement in Resistance to Targeted Treatment and Immunotherapy

“…Most importantly, tumors release a continuous amount of immunomodulatory EVs, which can become massive during cytotoxic treatment [68]. Cancer cells can intensify their production of immunosuppressive EVs during the onset of resistance to anti-PDL1 immunotherapy [69]. Tumor-antigen-carrying EVs might be the vehicle by which the immune system spots the presence of cancer cells, and the parallel screening for antigenic EV could bring a great promise for the diagnosis of immune responsive tumors [67].…”

“…Presence of interferon-γ (INF-γ) in the microenvironment stimulates the production of these immunosuppressive EVs and, in patients, circulating levels of EV PD-L1 that increase parallel to the levels of INF-γ, and can be used to stratify clinical responders to the PD-1 inhibitor pembrolizumab and non-responders [71]. PD-L1 is present on the surface of EVs isolated from the plasma of NSCLC patients, and the number of PD-L1-positive EVs correlates with PD-L1 expression level in the tumor tissue from the same patient [69]. PD-L1-expressing EVs that are derived from NSCLC cells can induce apoptosis of T lymphocytes, promoting tumor growth in mice.…”

“…PD-L1-expressing EVs that are derived from NSCLC cells can induce apoptosis of T lymphocytes, promoting tumor growth in mice. In this context, it seems that these EVs inhibit the secretion of INF-γ from Jurkat T cells to maintain a circuit of immune inactivation [69]. Tumor-derived EVs are also capable of inducing the expression of PD-L1 on monocytes, via transfer of tumor-cell specific noncoding RNAs, to facilitate immune escape accompanied by concurrent release of cytokines that contribute to cancer-related inflammation [72].…”