Cooling inflammation while potentiating immune checkpoint inhibition: Enhancing the benefit–risk ratio of immuno-oncology therapy

Balancing antitumor activity and suppression of inflammatory toxicities of immuno-oncology therapy has been an elusive goal of cancer therapeutics. Immune checkpoint inhibition (ICI) has demonstrated considerable promise in more than 10 solid tumor types but carries with it considerable risk of autoimmune toxicities. For some time, it has been known that epoxy-fatty acids (EpFA) play a role in the modulation of cancer-associated inflammation. Kelly et al. (1, this issue) found that pharmacological inhibition of the soluble epoxide hydrolase (sEH) pathway alone or in combination with ICI can suppress a pro-inflammatory tumor microenvironment (TME) associated with tumor progression. These observations motivate trials of ICI in combination with anti-inflammatory modulation of the sEH pathway to accomplish two goals: promotion of antitumor activity and suppression of autoimmunity. Clinical therapeutic strategies using soluble epoxide hydrolase inhibitors (sEHIs) in combination with ICI may provide a new perspective to address autoimmune toxicity while promoting anti-tumor efficacy.

Translational Relevance

A study by Kelly et al. (1) uses the combination of PUFA (polyunsaturated fatty acid) and sEHI to elucidate a strategy to potentiate immune checkpoint therapy while potentially reducing toxicity: They find that pharmacological inhibition of the sEH pathway alone or in combination with ICI suppresses inflammatory and tumorigenic cytokine release (Fig. 1).

Fig. 1.

Enhancing cancer immunotherapy via inhibition of sEH. (A) Dietary omega-3 PUFAs provide pro-resolving lipid mediators, but their loss due to sEH promotes an inflammatory environment. (B) sEH inhibitors reverse inflammatory processes by increasing cytotoxic T cell recruitment and SPM enhancement of anti-tumor activity. Reduction of pro-inflammatory cytokines may also reduce ICI toxicities and improve therapeutic efficacy.

Kelly et al. found that pharmacological inhibition of the soluble epoxide hydrolase (sEH) pathway alone or in combination with immune checkpoint inhibition (ICI) can suppress a pro-inflammatory tumor microenvironment (TME) associated with tumor progression.

Omega 3 (ω-3) vs. Omega 6 (ω-6) and Why It Matters

ω-3 PUFAs including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been implicated as anti-inflammatory through their epoxy metabolites (EpFA) EEQ (epoxyeicosatetraenoic acid) from EPA and EDP (epoxydocosapentaenoic acid) from DHA. These epoxy metabolites are involved in the inhibition of tumor growth in part, through suppression of angiogenesis, tumor metabolism, and metastasis (Fig. 1A) (2), but their mechanisms of action are complex, not fully understood, and may reflect the balance of ω-3 vs. ω-6 PUFAs (3). In contrast, epoxy metabolites of ω-6 PUFAs [epoxyeicosatrienoic acids (EETs)] from arachidonic acid (AA) have been implicated in tumor escape from dormancy, growth, and metastasis (4), in part, through promotion of angiogenesis (4) and cancer cell-intrinsic proliferation (5, 6). A critical feature of ω-3 PUFAs is their direct inhibition of inflammation, their oxidation to ω-3 fatty acid epoxides which are inflammation resolving, and their oxidation to resolvins, or specialized pro-resolving mediators (SPMs) that inhibit inflammation (7). Furthermore, the pharmacologic activity of sEHI’s enhances the stability of SPMs that resolve inflammation, in part, through reduction of inflammatory macrophage activation (Fig. 1B) (8). Also, ω-3 fatty acids are poor substrates for conversion into inflammatory prostaglandins and thromboxanes. Epoxides of ω-6 PUFAs derived from AA also are strongly inflammation resolving, but AA is also an excellent substrate to produce inflammatory chemical mediators such as prostaglandins as well. Thus, ω-6 PUFAs tend to promote inflammatory phenotype and the ratio of ω-3/ω-6 appears to empirically drive the balance between resolution and promotion of inflammation (9). Therefore, the influence of dietary balance and supplementation of ω-3/ω-6PUFAs in tumor control vs. progression is likely to be important (3, 10).

PUFA Signaling through Epoxide Generation and Hydrolysis

Signaling of ω-3 and ω-6 PUFA occurs, in part, through the generation of oxidation products through the cyclooxygenase, lipoxygenase, and cytochrome P450 oxidase pathways. Relevant for this discussion are the P450 pathways that irreversibly generate PUFA epoxides which in turn are irreversibly degraded to less active or pro-inflammatory dihydroxyl products (11). Epoxide formation and hydrolysis, in contrast to phosphorylation pathways, results in an irreversible direction of signaling. Furthermore, the intracellular and extracellular control of the P450 products are subject to degradation, in particular by sEH which regulates their biological activity in time, space, and tissue (12). sEH hydrolyzes epoxides to vicinal diols that may exhibit counterbalancing activity, thus providing a boundary of PUFA epoxide activity, in part, related to the irreversible nature of this hydrolysis (13). While much of the downstream signaling of PUFA epoxides is attributed to their binding to G protein–coupled receptors that promote some of their effector functions (14), much is unknown with regard to the pleiotropic signaling by PUFA epoxides.

Modeling the PUFA Ratio in Mice

Because of the differing effects of ω-3 and ω-6 epoxides in angiogenesis (2, 4) and other aspects of tumor biology (5, 6) (Fig. 1), pre-clinical animal models are important to inform clinical trials. To test the biological effects of increasing the ratio between ω-3 vs. ω-6 PUFA, the Fat-1 transgenic mice were developed to express the fat-1 gene of Caenorhabditis elegans, a fatty acid desaturase that converts ω-6 PUFA to ω-3, thereby significantly increasing the ω-3/ω-6 PUFA ratio. Kelly et al. (1) use this Fat-1 model to promote activity of an anti-PD-1 antibody in the RM-1 prostate cancer mouse model consistent with the activity obtained with an ω-3 diet and the anti-PD-1 antibody, thereby providing genetic support for the hypothesis that the balance between ω-3 and ω-6 is important for promotion of the immune checkpoint inhibitory activity of the anti-PD-1 antibody. This result is particularly striking because of the underlying immune depleted or “cold” TME associated with this model, resembling human prostate cancer. Also notable is the sEHI-associated increase in intratumoral T cells in a mouse bladder cancer model (1).

Expanding on the Fat-1 model, these transgenic mice and sEHI-treated mice are protected from colitis and autoimmune toxicities associated with PD-1 antibody therapy. Furthermore, Kelly et al. (1) observe that with sEHI treatment, there is a reduction of circulating cytokine mediators in the MB49 and B16 F10 melanoma models. Although these measurements are of circulating mediators, these findings raise the possibility that autoimmunity may be dampened by a predominance of ω-3 fatty acids or their resolving EpFA products (Fig. 1B).

Avenues to Clinical Development

Prior to translation to early-stage cancers, a phase Ib trial would be required to test a strategy of merging of sEHI’s with IO approaches in metastatic cancer. For example, it may be possible to test a PD-1 antibody/chemotherapy strategy with sEHI and ω-3 PUFA treatment and monitor rates of autoimmune toxicities. Reduction of rates of ICI toxicities such as type I diabetes, adrenal insufficiency, thyroiditis, arthritis, colitis, and pneumonitis in a metastatic cancer pilot study, (possible schema in Fig. 1B), could then lead to a Bayesian phase 2 neoadjuvant platform trial in early cancer using pathologic complete response as the primary endpoint and aggregate rates, grades, duration, and types of autoimmune events as secondary endpoints. Notably, ICI-associated autoimmunity events are stochastic and unpredictable. While there are no laboratory biomarkers predicting ICI toxicity, the development of a successful strategy to suppress ICI toxicity may also provide a strategy for biomarker discovery. If suppression of chemokine/cytokine profiles by an ω3-PUFA/sEHI combination correlates with suppression of rates of ICI-associated autoimmunity, certain chemokine/cytokine profiles might emerge as useful biomarkers that predict ICI toxicity. A challenge with this type of trial would be tolerability and compliance with dietary ω-3 PUFA supplementation and sEHI treatment in patients undergoing ICI therapy. Rates of tolerance, compliance, and quality of life would need to be monitored in such a phase 1b trial. Candidate predictive biomarkers for toxicities could be measured before and after initiation of ICI therapy with and without ω-3 PUFA supplementation and sEHI treatment.

Implications for Prostate Cancer

There has been interest in the roles of ω-3 PUFA in prostate cancer, and of the models studied by Kelly et al., the prostate cancer studies may provide a perspective linking these new studies with prior work. The RM-1 murine prostate cancer model is considered to be immunologically “cold” which makes combinations of PD-1 antibody and PUFA/sEHI of great interest. Indeed, human prostate cancers are generally among the coldest solid tumors (15), and no ICI agent has yet garnered FDA approval for patients with advanced prostate cancer (16) (except in the very small subset harboring DNA mismatch repair deficiency and/or microsatellite instability) (17). Having said that, there is modest activity of ICI agents in prostate cancer [about 10% response rates using anti-PD-1 alone (18), and about 20% response rates using anti-PD-1 plus anti-CTLA4] (19), but this has been insufficient to result in FDA approval. In this context, an ICI-based combination incorporating sEHI and PUFA would be very attractive, both from the safety perspective (potentially less immune-related toxicities) but also from the efficacy perspective in prostate cancer. Thus, relative to many other cancers in which one or more ICI agents are already part of the therapeutic armamentarium, the unmet need in prostate cancer appears to be particularly high since ICI is not currently part of the treatment arsenal (20).