IDO Vaccine Ablates Immune-Suppressive Myeloid Populations and Enhances Antitumor Effects Independent of Tumor Cell IDO Status

Abstract

The immunosuppressive tumor microenvironment (TME) does not allow generation and expansion of anti-tumor 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 (MDSCs) and dendritic cells (DCs) 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 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. IDO-vaccine significantly enhanced the anti-tumor 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 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. 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.

Tumor microenvironment antigens

“…For example, co-activation of IDO-specific, cytotoxic T cells boosted T cell immunity towards both viral and tumor-associated antigens. Similar effects was described in an animal model of cancer, in which IDO-based vaccination significantly enhanced immune responses against other tumor antigen-specific vaccines by downregulating IDO-expressing cell numbers in the TME [74].…”

YH29407 with anti-PD-1 ameliorates anti-tumor effects via increased T cell functionality and antigen presenting machinery in the tumor microenvironment

“…Since its discovery, IDO has contributed to important research outcomes and achievements ( Sharma et al, 2021 ; Zhai et al, 2021 ; Zhang et al, 2021 ; Nandre et al, 2022 ). It is well known that the IDO enzyme, which converts tryptophan, an essential amino acid, into Kyn, inhibits cells such as CD8 + T cells, NK cells, and macrophages, activates regulatory T cells, and has positive effects on tumor progression ( Mbongue et al, 2015 ; Zhai et al, 2020 ).…”

Strategies to overcome myeloid cell induced immune suppression in the tumor microenvironment

“…Overexpression of IDO1 is considered an important driver of tumor associated immune suppression and a key to establishing immune tolerance of cancer antigens ( 179 , 180 ). High intratumoral IDO1 expression is correlated with poor prognosis in melanoma, ovarian cancer, colorectal cancer, and lung cancers ( 181 , 182 ). In ovarian cancer, high IDO1 expression also correlates with increased drug resistance ( 183 ).…”