Genetic Pathways Influence Response to Immunotherapy in Patients with Melanoma

By Cameron Kelsall, MD /alert Contributor

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Genetic variation in IL7 expression may be linked to increased immune-related adverse events in patients receiving immune checkpoint blockade for melanoma, according to research published in Nature Medicine

Although immunotherapy has revolutionized the treatment landscape for patients with melanoma, autoimmune complications regularly accompany immune checkpoint blockade, with few predictive risk factors identified. Benjamin P. Fairfax, MBChB, PhD, associate professor of oncology at University of Oxford, and colleagues conjecture that rs16906115, a non-coding polymorphism of IL7, correlated with immune-related toxicities in patients treated with immune checkpoint blockade. 

In a prospective cohort of 214 patients, Fairfax and colleagues observed an rs16906115 minor allele frequency of 7.4%. These patients had a significantly increased likelihood of developing severe immune-related adverse events (grade 3 or higher) prior to the fifth treatment cycle (OR = 2.24; 95% CI, 1.03-5.09; P = .046). 

Among patients receiving single-agent anti-PD-L1 therapies, rs16906115 was associated with a significantly likelihood of developing severe immune-related adverse events before the fifth treatment cycle (OR = 6; 95% CI, 1.5-23; P = .0084), as well as immune-related adverse events requiring steroid therapy at any point during treatment (OR = 4.4; 95% CI, 1.2-15.1; P = .019). The researchers determined that rs16906115 plays a role in the regulation of B-cell IL7 expression in this patient population. 

“Although circulating immune cells are not generally recognized to produce IL-7, we found that peripheral blood isolated CD19-positive B cells robustly express IL7 at levels greatly in excess of other cell subsets,” Fairfax and colleagues wrote. “Notably, IL7 expression in pre-treatment patient-derived B cells was significantly induced compared to that in B cells from healthy controls (94 controls and 92 patients; mean log2 expression, 8.3 FKPM vs 8.87 FKPM, P = 5.9x10−6), with this effect not apparent across other subsets and independent of age.” 

Patients carrying the rs16906115 risk allele demonstrated upregulated B-cell IL7 expression prior to treatment and throughout the treatment period, a factor not replicated in other cell types. Pretreatment B-cell IL7 was significantly associated with immune-related adverse events in analyses that controlled for rs16906115 (P = .0092) and included patients carrying the reference allele (P = .0087). 

IL7 expression was further associated with B-cell maturation. “We noted genotypic association of rs16906115 status, with risk allele carriers demonstrating an increased percentage of mutations in IGH, IGK and IGL chains in pre-treated patients,” the researchers wrote. “Similarly, risk allele carriers showed reduced numbers of IGHD-expressing B cell clones pre-treatment, indicating a pre-existent state of B cell immunoglobulin class switching and reduced B cell naivety in these individuals.” 

An analysis of pre-treatment B cells from 24 patients with melanoma found high expressions of IL7 in unswitched memory cells and switched memory cells, as well as reduced IGHD expression and IGHM upregulation compared to healthy controls. The researchers observed a link between rs16906115 and T-cell responses. Carriers exhibited increased numbers of terminally differentiated effector memory T cells that re-expressed CD45RA T cells, while also a decline in naive T cells following treatment. The most significant decline in naive T cells was observed in patients in the CD8-positive subset (P = .00017). 

An analysis of CD8-positive clone sizes underscored the relationship between rs16906115 and response. “We found a significant interaction between immune checkpoint blockade treatment and genotype in the change in Gini in response to treatment, with risk allele carriers showing increased clonal inequality post-treatment, resultant in skewed clonality after immune checkpoint blockade treatment according to allele,” the researchers wrote. “We found that risk allele carriers post single-agent immune checkpoint blockade had a repertoire composed of proportionally fewer small clones (< 0.05% repertoire in size) and, instead, demonstrated significantly greater repertoire occupancy by large clones (> 0.5% repertoire in size) after both combined and single-agent immune checkpoint blockade.” However, presence of the allele was associated with increases in progression-free survival (P = .016), disease-free survival (P = .015), and overall survival (P = .014). 

“The finding of improved disease-specific and overall survival in patients with melanoma carrying the risk allele in the Cancer Genome Atlas dataset indicates that IL-7 plays a role in the natural history of melanoma and further highlights the potential therapeutic importance of this pathway,” the researchers concluded. “This study highlights the power of agnostic genetic analyses to provide insights into human immunity of high relevance to disease and delineates a key role for IL-7 in response to immune checkpoint blockade, revitalizing previous proposals for incorporating this molecule as a potential adjunct to immunotherapy strategies.” 


Disclosures: Some authors declared financial ties to drugmakers. See full study for details. 

Photo Credit: Getty Images. 


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