Two studies point to blood levels of the proinflammatory cytokine IL8 as a negative prognostic indicator of responses in patients receiving immune checkpoint inhibitors. The findings provide a compelling rationale for combining selective inhibitors of the IL8 axis with PD-1 pathway–directed drugs.

Patients with elevated levels of the proinflammatory cytokine IL8 in their blood tend to fare worse on immune checkpoint inhibitors, according to two large retrospective studies that examined responses across a range of tumor types.

Although prospective validation is still needed, the findings highlight the potential of circulating IL8 as a biomarker to guide treatment decisions for patients undergoing checkpoint blockade therapy. The results also provide a compelling rationale for combining selective inhibitors of IL8 or its receptors with immunotherapeutics directed at the PD-1 pathway.

“This does say that there's something to the biology there,” says James Gulley, MD, PhD, of the NCI, who was not involved in either study.

In one, a team evaluated pretreatment IL8 levels in serum from 1,344 patients with skin, lung, and kidney cancers (Nat Med 2020:26;688–92). Patients had received Bristol-Myers Squibb's PD-1 inhibitor nivolumab (Opdivo), either alone or in combination with the company's CTLA4 inhibitor ipilimumab (Yervoy). The researchers found that patients with IL8 levels above the median were less likely to respond to treatment and more than twice as likely to die at any time point than those with IL8 levels below the median.

A Genentech-led team came to much the same conclusion in an analysis of plasma IL8 in a separate group of 1,445 patients with urothelial and kidney cancers treated with the company's anti–PD-L1 drug atezolizumab (Tecentriq; Nat Med 2020:26;693–8).

“The signal, if you look at the two manuscripts, is very strong,” says Kurt Schalper, MD, PhD, of Yale School of Medicine in New Haven, CT, co–first author of the nivolumab/ipilimumab study. “It's also very consistent across tumors with really different biologies.”

The IL8-mediated effect on survival was independent of other proposed immunotherapy biomarkers, such as PD-L1 expression and tumor mutation burden, both groups found. Plus, each team traced the source of elevated IL8 production to populations of myeloid cells that suppress T-cell activity.


IL8 crystal structure.

Schalper's group, for example, documented a consistent correlation between serum IL8 levels and the numbers of infiltrating neutrophils and monocytes in tumor samples. The Genentech-led atezolizumab team used single-cell RNA sequencing to show that IL8-producing myeloid cells—both within peripheral blood and within tumors—expressed high levels of other proinflammatory genes and low levels of genes involved in antigen presentation and interferon signaling.

The results of both studies point to high IL8 expression as an indicator of a myeloid-enriched tumor microenvironment and suggest that targeting the IL8 axis could help reverse this immunosuppressive milieu to enhance T-cell responsiveness. Combination trials are testing whether IL8 inhibitors, such as HuMax-IL8 (Bristol-Myers Squibb), or drugs directed at IL8 receptors—including the CXCR2 inhibitors navarixin (Merck) and AZD5069 (AstraZeneca) and the CXCR1/2 inhibitor SX-682 (Syntrix)—can enhance the efficacy of PD-1– or PD-L1–targeted therapies.

Meanwhile, Gulley's team is planning a trial that will combine SX-682 with bintrafusp alfa (Merck KGaA), a bifunctional fusion protein that simultaneously targets PD-L1 and traps TGFβ in the tumor microenvironment. A recent preclinical study led by the NCI's Claudia Palena, PhD, found that neutralization of TGFβ signaling alongside CXCR1/2 blockade helped enhance antitumor immune responses to PD-L1 inhibition (J Immunother Cancer 2020;8:e000326).

Gulley acknowledges that dual blockade of the IL8 and PD-1 pathways “is a step in the right direction.” However, he adds, “we may require additional combination approaches that really take into account all of the other things going on in the tumor microenvironment.” –Elie Dolgin

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