Abstract
The immunosuppressive tumor microenvironment (TME) does not allow generation and expansion of antitumor effector cells. One of the potent immunosuppressive factors present in the TME is the indoleamine-pyrrole 2,3-dioxygenase (IDO) enzyme, produced mainly by cancer cells and suppressive immune cells of myeloid origin. In fact, IDO+ myeloid-derived suppressor cells (MDSC) and dendritic cells (DC) tend to be more suppressive than their IDO- counterparts. Hence, therapeutic approaches that would target the IDO+ cells in the TME, while sparing the antigen-presenting functions of IDO- myeloid populations, are needed. Using an IDO-specific peptide vaccine (IDO vaccine), we explored the possibility of generating effector cells against IDO and non-IDO tumor-derived antigens. For this, IDO-secreting (B16F10 melanoma) and non-IDO-secreting (TC-1) mouse tumor models were employed. We showed that the IDO vaccine significantly reduced tumor growth and enhanced survival of mice in both the tumor models, which associated with a robust induction of IDO-specific effector cells in the TME. The IDO vaccine significantly enhanced the antitumor efficacy of non-IDO tumor antigen-specific vaccines, leading to an increase in the number of total and antigen-specific activated CD8+ T cells (IFNγ+ and granzyme B+). Treatment with the IDO vaccine significantly reduced the numbers of IDO+ MDSCs and DCs, and immunosuppressive regulatory T cells in both tumor models, resulting in enhanced therapeutic ratios. Together, we showed that vaccination against IDO is a promising therapeutic option for both IDO-producing and non-IDO-producing tumors. The IDO vaccine selectively ablates the IDO+ compartment in the TME, leading to a significant enhancement of the immune responses against other tumor antigen-specific vaccines.
Original language | English (US) |
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Pages (from-to) | 571-580 |
Number of pages | 10 |
Journal | Cancer Immunology Research |
Volume | 10 |
Issue number | 5 |
DOIs | |
State | Published - May 2022 |
Bibliographical note
Funding Information:We are grateful to Jeannie and Tony Loop for their generous support to SNK’s laboratory. We acknowledge the Flow Cytometry & Cell Sorting Shared Resource in Georgetown University, which is partially supported by NIH/NCI grant P30-CA051008 and NIH S10 grant, S10OD016213.
Funding Information:
M.H. Andersen reports personal fees from IO Biotech during the conduct of the study; grants and personal fees from IO Biotech outside the submitted work; in addition, M.H. Andersen has a patent for INDOLEAMINE 2,3-DIOXYGENASE BASED IMMUNOTHERAPY issued. A.W. Pedersen reports other support from IO Biotech ApS during the conduct of the study; other support from IO Biotech ApS outside the submitted work. M.-B. Zocca reports personal fees and other support from IO Biotech during the conduct of the study; personal fees from Valo Therapeutics outside the submitted work. S.N. Khleif reports grants and other support from
Publisher Copyright:
© 2022 The Authors
Keywords
- Animals
- Antigens, Neoplasm
- Cancer Vaccines
- Indoleamine-Pyrrole 2,3,-Dioxygenase
- Melanoma/drug therapy
- Mice
- Tumor Microenvironment
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Journal Article
- Research Support, N.I.H., Extramural