Chemotherapy Dose Shapes the Expression of Immune-Interacting Markers on Cancer Cells

• Published in: Cellular and molecular bioengineering Vol. 15; no. 6; pp. 535 - 551
• Main Authors: Najibi, Alexander J., Larkin, Kerry, Feng, Zhaoqianqi, Jeffreys, Nicholas, Dacus, Mason T., Rustagi, Yashika, Hodi, F. Stephen, Mooney, David J.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2022; Springer Nature B.V
• Subjects: Anthracycline; Antigens; Biological and Medical Physics; Biomaterials; Biomedical Engineering and Bioengineering; Biomedical Engineering/Biotechnology; Biophysics; Bone marrow; Breast cancer; Calreticulin; Cancer therapies; Cell Biology; Cell death; Cell surface; Chemotherapy; Cytotoxicity; Dendritic cells; Doxorubicin; Engineering; Exposure; Hydrogels; Immune system; Immunogenicity; Immunotherapy; Leukemia; Major histocompatibility complex; Melanoma; Original; Original Article; Ovalbumin; PD-L1 protein; Tumor cells; Tumors; Controlled drug release; Doxorubicin; Tumor immune interaction; Chemo-immunotherapy
• ISSN: 1865-5025; 1865-5033
• DOI: 10.1007/s12195-022-00742-y

Introduction Tumor and immune cells interact through a variety of cell-surface proteins that can either restrain or promote tumor progression. The impacts of cytotoxic chemotherapy dose and delivery route on this interaction profile remain incompletely understood, and could support the development of more effective combination therapies for cancer treatment. Methods and Results Here, we found that exposure to the anthracycline doxorubicin altered the expression of numerous immune-interacting markers (MHC-I, PD-L1, PD-L2, CD47, Fas, and calreticulin) on live melanoma, breast cancer, and leukemia cells in a dose-dependent manner in vitro . Notably, an intermediate dose best induced immunogenic cell death and the expression of immune-activating markers without maximizing expression of markers associated with immune suppression. Bone marrow-derived dendritic cells exposed to ovalbumin-expressing melanoma treated with intermediate doxorubicin dose became activated and best presented tumor antigen. In a murine melanoma model, both the doxorubicin dose and delivery location (systemic infusion versus local administration) affected the expression of these markers on live tumor cells. Particularly, local release of doxorubicin from a hydrogel increased calreticulin expression on tumor cells without inducing immune-suppressive markers, in a manner dependent on the loaded dose. Doxorubicin exposure also altered the expression of immune-interacting markers in patient-derived melanoma cells. Conclusions Together, these results illustrate how standard-of-care chemotherapy, when administered in various manners, can lead to distinct expression of immunogenic markers on cancer cells. These findings may inform development of chemo-immunotherapy combinations for cancer treatment.