The immune checkpoint molecule CD70 and its receptor CD27 are aberrantly expressed in many hematological and solid malignancies. Dysregulation of the CD70-CD27 axis within the tumor and its microenvironment is associated with tumor progression and immunosuppression. This is in contrast to physiological conditions, where tightly controlled expression of CD70 and CD27 plays a role in co-stimulation in immune responses. In hematological malignancies, cancer cells co-express CD70 and CD27 promoting stemness, proliferation and survival of malignancy. In solid tumors, only expression of CD70 is present on the tumor cells which can facilitate immune evasion through CD27 expression in the tumor microenvironment. The discovery of these tumor promoting and immunosuppressive effects of the CD70-CD27 axis has unfolded a novel target in the field of oncology, CD70.In this review, we thoroughly discuss current insights into expression patterns and the role of the CD70-CD27 axis in hematological and solid malignancies, its effect on the tumor microenvironment and (pre)clinical therapeutic strategies.

The concept of immunogenic cell death (ICD) has emerged as a cornerstone of therapy-induced anti-tumor immunity. To this end, the following chemotherapies were evaluated for their ability to induce ICD in non-small cell lung cancer (NSCLC) cell lines: docetaxel, carboplatin, cisplatin, oxaliplatin and mafosfamide. The ICD hallmarks ATP, ecto-calreticulin, HMGB1, phagocytosis and maturation status of dendritic cells (DCs) were assessed in vitro. Furthermore, an in vivo vaccination assay on C57BL/6J mice was performed to validate our in vitro results. Docetaxel and the combination of docetaxel with carboplatin or cisplatin demonstrated the highest levels of ATP, ecto-calreticulin and HMGB1 in three out of four NSCLC cell lines. In addition, these regimens resulted in phagocytosis of treated NSCLC cells and maturation of DCs. Along similar lines, all mice vaccinated with NSCLC cells treated with docetaxel and cisplatin remained tumor-free after challenge. However, this was not the case for docetaxel, despite its induction of the ICD-related molecules in vitro, as it failed to reject tumor growth at the challenge site in 60% of the mice. Moreover, our in vitro and in vivo data show the inability of oxaliplatin to induce ICD in NSCLC cells. Overall with this study we demonstrate that clinically relevant chemotherapeutic regimens in NSCLC patients have the ability to induce ICD.

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Introduction. Accumulating evidence suggests that the clinical success of chemotherapy is not only attributed to direct tumor cell toxicity, but also relies on its anti-tumor effects by immunomodulation. In this regard, the concept of immunogenic cell death (ICD) has emerged as a cornerstone of therapy-induced anti-tumor immunity. To this end, we assessed different chemotherapeutic agents on their ability to induce ICD in vitro and in vivo in non-small cell lung cancer (NSCLC). Material and methods. NSCLC cell lines (NCI-H1975, A549, NCI-H1650 and LLC) were treated with the IC50 of different chemotherapeutic agents: docetaxel (DOC), carboplatin (CARBO), cisplatin (CDDP), oxaliplatin (OXA) and mafosfamide (MF). In addition, combinations of DOC (IC50) with CARBO (IC40) or CDDP (IC40) were included. Release of important damage-associated molecular patterns (DAMPs) was evaluated: ATP (bioluminescence), ecto-CRT (flow cytometry) and HMGB1 (ELISA) after 24h, 48h and 72h of treatment, respectively. In addition, phagocytosis and maturation status of dendritic cells (DCs) were assessed. Finally, a vaccination assay was performed to validate in vitro findings using 6-week old female C57BL/6J mice (5 mice/condition). Mice were vaccinated twice (1 × 106 treated cells/mouse) before receiving the challenge (5 × 104 live cells/mouse). Results. Three out of four NSCLC cell lines (NCI-H1975, A549 and LLC) showed significant higher levels of ATP, ecto-CRT and HMGB1 after treatment with DOC, DOC+CARBO and DOC+CDDP compared to vehicle. In addition, phagocytosis of treated tumor cells and maturation (CD86) of DCs were significantly increased in all three human NSCLC cell lines after treatment with the above-mentioned chemotherapeutic regimens. Furthermore, murine LLC cells treated with DOC, MF, DOC+CARBO and DOC+CDDP resulted in a significant release of all three DAMPs in vitro, as opposed to treatment with OXA. Along similar lines, 0%, (DOC+CDDP), 20% (MF and DOC+CARBO) and 80% (OXA) of the mice developed a tumor at the challenge site in vivo. This was not the case for treatment with DOC, which resulted in tumor growth at the challenge site in 60% of the mice. Conclusion. Overall, these findings demonstrate the immunostimulatory effects of clinically relevant chemotherapeutic regimens, especially DOC+CARBO and DOC+CDDP, making it worthwhile to investigate these agents in combination strategies with immunotherapy in NSCLC. Citation Format: Tal Flieswasser, Jinthe Van Loenhout, Laurie Freire Boullosa, Astrid Van den Eynde, Jorrit De Waele, Jonas Van Audenaerde, Filip Lardon, Evelien Smits, Patrick Pauwels, Jacobs Julie. Immunogenic properties of chemotherapeutic agents in the treatment of non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2414.