How might COX-2 inhibitors, a potent class of painkillers help immunotherapies fight cancer?

Over the past three decades, a deeper understanding of the mechanisms underlying the generation of tumor immunity has provided a framework for developing more potent immunotherapies. One major insight is that combination approaches that address multiple defects in the host response are likely to be required for clinical efficacy.

We know that immune regulatory pathways/cells and tumor derived factors impede an effective antitumor immunotherapeutic response. Strategies to break these immunosuppressive mechanisms responsible for tumor immune escape is a key goal for any effective anticancer immunotherapy. One such strategy involves the use of nonsteroidal anti-inflammataory drugs (NSAIDs.)

The main therapeutic target of NSAIDs is the enzyme cyclooxygenase (COX. There are two isoforms of COX: COX-1 is implicated in cellular regulation while COX-2 is implicated in several physiological responses, including angiogenesis and metastasis. COX-2 is overexpressed in most solid tumors, and selective COX-2 inhibitors can inhibit cell proliferation, tumor invasiveness, and angiogenesis, while simultaneously apoptosis (cell death), drug resistance and suppressing immune responses.

The impact of COX-2 inhibitors in reducing cancer and cancer risk, and improving survival in several types of cancer, is well established. This impact is observed either alone or in combination with other therapies, such as immunotherapy. Although the underlying mechanisms of these chemo-preventive effects have not yet been fully elucidated, some studies have shown that specific COX-2 inhibitors can increase the infiltration of CD4+ and CD8+ T cells to tumor sites, thus positively regulating the tumor specific host immune response.

Moreover, by inhibiting prostaglandin E2 (PGE2), a key immuno-suppressor, COX inhibitors can also modulate the activity of T-regulatory cells, tumor-associated macrophages, and myeloid-derived suppressor cells. So it would seem they might be a good partner for immunotherapies, such as checkpoint inhibitors, in fighting cancer. 

Yet despite the positive results, very few studies have addressed the potential for NSAIDs in combination with cancer immunotherapies. One recent study reported that administering aspirin in combination with immunotherapy could enhance the efficacy of treatment. Researchers reported that skin, bowel and breast cancer can produce large amounts of PGE2, resulting in a reduction of the immune system’s ability to attack aberrant cells, allowing cancers to hide from immuno-surveillance. Preclinical data demonstrate that inhibiting COX synergizes with anti-PD-1 blockades in inducing eradication of tumors. This implies that COX inhibitors could be useful adjuvants for immune-based therapies in cancer.

This preliminary data warrants further investigation. Combination strategies are rapidly emerging as a new paradigm for cancer therapy. COX-2 inhibition offer a nontoxic, readily available approach that needs to be evaluated in combination with current immunotherapies.

This post was adapted from an article that appeared today in MedCrave Online Journal’s Immunology.