DHODH Inhibition Enhances Immune Checkpoint Blockade Efficacy by Increasing Cancer Cell Antigen Presentation

核心概念

Inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine biosynthesis pathway, induces robust upregulation of antigen presentation pathway genes and increases tumor cell surface MHC-I expression, thereby enhancing the efficacy of immune checkpoint blockade in a preclinical melanoma model.

摘要

The authors examined the cellular response to DHODH inhibition and found that treatment with the DHODH inhibitor brequinar (BQ) or the clinically approved DHODH inhibitor teriflunomide led to a dose- and duration-dependent upregulation of genes involved in the antigen presentation pathway (APP) and increased cell surface expression of MHC-I across diverse cancer cell lines.

This effect was strictly dependent on pyrimidine nucleotide depletion, as it was abrogated by supplementation with the pyrimidine nucleoside uridine. Mechanistic studies revealed that the APP induction was independent of canonical regulators like IFN-JAK-STAT, NF-κB, and cGAS-STING-TBK1 pathways, but required the activity of the positive transcription elongation factor B (P-TEFb), which controls RNA polymerase II elongation.

In a syngeneic mouse melanoma model, BQ monotherapy showed impressive single-agent efficacy and significantly prolonged survival when combined with dual immune checkpoint blockade (anti-CTLA-4 and anti-PD-1) in a sequential treatment regimen, but not when administered concurrently. These results demonstrate that DHODH inhibition can enhance cancer immunotherapy by increasing tumor antigen presentation and provide a rationale for combining DHODH inhibitors with immune checkpoint blockade.

統計資料

Brequinar treatment caused a rapid and dose-dependent depletion of pyrimidine nucleotides UTP and CTP in CFPAC-1 and B16F10 cancer cells.
Brequinar treatment led to a 2-4 fold increase in mRNA levels of MHC-I heavy chain genes (HLA-A, HLA-B, HLA-C) across diverse human cancer cell lines.
Brequinar treatment increased cell surface MHC-I levels by 2-3 fold in CFPAC-1 and B16F10 cancer cells.

引述

"Pyrimidine nucleotide depletion triggers the expression of innate immunity-related genes and induces an interferon-like response."
"High tumoral expression of MHC-I, MHC-II, and other APP genes correlates with better overall survival in patients with melanoma treated with ICB therapies."
"Enforced MHC-I upregulation by various interventions can facilitate anticancer immunity and enhance the efficacy of immune checkpoint blockade."

從以下內容提煉的關鍵洞見

DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation

by Mullen,N. J.... 於 www.biorxiv.org 04-05-2023

https://www.biorxiv.org/content/10.1101/2023.04.03.535399v2

深入探究

How might the timing and sequencing of DHODH inhibitor and immune checkpoint blockade administration be optimized to further improve therapeutic outcomes

To optimize therapeutic outcomes, the timing and sequencing of DHODH inhibitor and immune checkpoint blockade administration should be carefully considered. One approach could involve pretreatment with the DHODH inhibitor to induce upregulation of antigen presentation pathway (APP) genes and increase MHC-I expression in cancer cells. This priming effect could potentially enhance the recognition of cancer cell antigens by T-cells, making the tumor more susceptible to immune checkpoint blockade. Following this priming phase, the administration of immune checkpoint blockade agents could then capitalize on the increased antigen presentation to mount a more effective immune response against the tumor cells. This sequential approach may allow for a synergistic effect between the DHODH inhibitor-induced antigen presentation and the immune checkpoint blockade, leading to improved therapeutic outcomes.

What are the potential mechanisms by which concurrent administration of DHODH inhibitor and immune checkpoint blockade may impair the anticancer immune response compared to sequential treatment

Concurrent administration of DHODH inhibitor and immune checkpoint blockade may potentially impair the anticancer immune response compared to sequential treatment due to several factors. One possible reason is that the DHODH inhibitor-induced upregulation of antigen presentation pathway genes and MHC-I expression may not be fully established at the time of immune checkpoint blockade administration in the concurrent approach. This could result in suboptimal antigen presentation and T-cell activation, limiting the effectiveness of the immune checkpoint blockade. Additionally, concurrent treatment may lead to potential interference between the mechanisms of action of the DHODH inhibitor and the immune checkpoint blockade agents, potentially dampening the overall immune response. Therefore, sequential treatment may allow for a more coordinated and synergistic interaction between the two therapies, leading to enhanced anticancer immunity and improved therapeutic outcomes.

Could targeting other nucleotide biosynthesis pathways, such as the de novo purine synthesis pathway, also enhance tumor antigen presentation and improve immunotherapy efficacy

Targeting other nucleotide biosynthesis pathways, such as the de novo purine synthesis pathway, could also enhance tumor antigen presentation and potentially improve immunotherapy efficacy. Purine nucleotides play a crucial role in various cellular processes, including DNA and RNA synthesis, energy metabolism, and signaling pathways. Inhibiting enzymes involved in purine biosynthesis, similar to DHODH inhibition in the pyrimidine pathway, could lead to nucleotide depletion and trigger cellular responses that enhance antigen presentation. By inducing changes in the cellular nucleotide pool, targeting the de novo purine synthesis pathway may also impact immune cell function and the tumor microenvironment, potentially modulating the immune response against cancer cells. Further research into the effects of targeting purine biosynthesis on antigen presentation and immunotherapy efficacy is warranted to explore the full therapeutic potential of this approach.