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Chemotherapy Dose Shapes the Expression of Immune-Interacting Markers on Cancer Cells
Alexander J Najibi1,2, Kerry Larkin1,2, Zhaoqianqi Feng1,2
1John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138 USA.
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.
Supplementary Information:
The online version contains supplementary material available at 10.1007/s12195-022-00742-y.
Insights
Chemotherapy dose and delivery impact cancer cell immune interactions. Intermediate doxorubicin doses promote anti-tumor immunity, guiding new chemo-immunotherapy strategies.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Tumor cells and immune cells communicate via surface proteins, influencing cancer progression.
- The effects of chemotherapy dose and delivery on these interactions are not fully understood.
- Optimizing these interactions could lead to better combination cancer therapies.
Purpose of the Study:
- To investigate how doxorubicin dose and delivery route affect immune-interacting markers on cancer cells.
- To determine the optimal doxorubicin treatment for inducing immunogenic cell death and immune activation.
- To explore the potential for chemo-immunotherapy development.
Main Methods:
- Exposed melanoma, breast cancer, and leukemia cells to varying doxorubicin doses in vitro.
- Assessed expression of immune markers (MHC-I, PD-L1, PD-L2, CD47, Fas, calreticulin).
- Evaluated dendritic cell activation and antigen presentation.
- Studied doxorubicin effects in a murine melanoma model and patient-derived cells.
Main Results:
- Doxorubicin altered immune marker expression in a dose-dependent manner.
- Intermediate doxorubicin doses induced immunogenic cell death and immune activation markers.
- Local doxorubicin delivery via hydrogel enhanced calreticulin expression without immune suppression.
- Doxorubicin affected immune marker expression in patient-derived melanoma cells.
Conclusions:
- Chemotherapy administration significantly alters cancer cell immunogenic marker expression.
- Findings support the strategic use of chemotherapy to enhance anti-tumor immune responses.
- Results provide a basis for developing novel chemo-immunotherapy combinations.
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