Tumor microenvironment changes implicated in clear cell RCC obesity paradox
medwireNews: Tumors from obese patients with clear cell renal cell carcinoma (RCC) have higher angiogenesis scores than those from normal-weight patients, as well as differences in the tumor microenvironment, US researchers report.
A Ari Hakimi (Memorial Sloan Kettering Cancer Center, New York) and colleagues believe their findings “lend biological support to the obesity paradox in clear cell RCC [and] could help to explain the survival advantage in obese patients versus those at a normal weight in this disease setting.”
Hakimi and team assessed data for obese (BMI ≥30 kg/m2) and normal weight (BMI 18.5–24.9 kg/m2) patients with clear cell RCC from The Cancer Genome Atlas (TCGA; n=93), the COMPARZ phase 3 clinical trial (n=256), and a Memorial Sloan Kettering (MSK) observational immunotherapy cohort (n=129).
During each of the study periods, mortality rates were consistently lower among obese patients than among those of normal weight, at 35% versus 76% in the TCGA cohort, 45% versus 59% in the COMPARZ cohort, and 38% versus 57% in the MSK immunotherapy cohort. However, after adjustment for risk factors, only the differences in the TCGA and COMPARZ cohorts were statistically significant.
Since these findings confirmed “the presence of the obesity paradox” among their cohorts, the researchers then investigated transcriptomic differences between primary tumors from patients in the obese and normal BMI groups.
They report in The Lancet Oncology that tumors from obese patients in the COMPARZ cohort had significantly upregulated hypoxia, TGF-β, epithelial–mesenchymal transition, and angiogenesis signaling pathways compared with those from normal-weight patients.
This “suggests activation of wound-healing pathways in obese patients,” Hakimi et al remark.
By contrast, the interferon-γ pathway was downregulated in the tumors from the obese patients and there were no significant differences in other inflammatory pathways, indicating that “tumours arising in an obesogenic environment do not seem to harbour increased local inflammation.”
Further analysis showed that obese patients in the COMPARZ cohort had lower expression of several immune checkpoint molecules including PD-L1 than the normal-weight patients, but the findings were not replicated in the TCGA cohort.
Finally, the researchers demonstrated that obese patients had higher immune infiltration and hypoxia gene-expression scores in the peritumoral fat than did normal weight patients, particularly in peritumoral fat near the tumor.
“Taken together, our initial mechanistic findings suggest that differences in the tumour microenvironment might underlie the apparent survival advantage of obese patients with clear cell RCC compared with patients at a normal weight that has been observed in clinical cohorts,” Hakimi and co-authors conclude.
They add that obesity could “create an environment that facilitates clear cell RCC growth via angiogenesis while simultaneously making these tumours more susceptible to tyrosine kinase inhibitors; and that increased angiogenesis could enhance local drug delivery.”
In an accompanying comment, Sebastiano Buti (University Hospital of Parma, Italy) and co-authors say that the study represents “a crucial step forward in our comprehension of the mechanisms underlying the obesity paradox in patients with RCC.”
They add: “The therapeutic implications of these hypothesis-generating findings merit careful consideration for the design of future clinical trials in this setting.”
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