Obesity induces limited changes to systemic and local immune profiles in treatment-naive human clear cell renal cell carcinoma

Abstract

Understanding the effects of obesity on the immune profile of renal cell carcinoma (RCC) patients is critical, given the rising use of immunotherapies to treat advanced disease and recent reports of differential cancer immunotherapy outcomes with obesity. Here, we evaluated multiple immune parameters at the genetic, soluble protein, and cellular levels in peripheral blood and renal tumors from treatment-naive clear cell RCC (ccRCC) subjects (n = 69), to better understand the effects of host obesity (Body Mass Index "BMI" � 30 kg/ m 2 ) in the absence of immunotherapy. Tumor-free donors (n = 38) with or without obesity were used as controls. In our ccRCC cohort, increasing BMI was associated with decreased percentages of circulating activated PD-1 + CD8 + T cells, CD14 + CD16 neg classical monocytes, and Foxp3 + regulatory T cells (Tregs). Only CD14 + CD16 neg classical monocytes and Tregs were reduced when obesity was examined as a categorical variable. Obesity did not alter the percentages of circulating IFNγ + CD8 T cells or IFNγ + , IL-4 + , or IL-17A + CD4 T cells in ccRCC subjects. Of 38 plasma proteins analyzed, six (CCL3, IL-1β, IL-1RA, IL-10, IL-17, and TNFα) were upregulated specifically in ccRCC subjects with obesity versus tumor-free controls with obesity. IGFBP-1 was uniquely decreased in ccRCC subjects with obesity versus non-obese ccRCC subjects. Immunogenetic profiling of ccRCC tumors revealed that 93% of examined genes were equivalently expressed and no changes in cell type scores were found in stage-matched tumors from obesity category II/III versus normal weight (BMI � 35 kg/m 2 versus 18.5-24.9 kg/m 2 , respectively) subjects.

Identification of a Prognostic Risk Signature of Kidney Renal Clear Cell Carcinoma Based on Regulating the Immune Response Pathway Exploration

“…Chang et al found that the high IL4 expression in KIRC is associated with increased tumor recurrence and decreased patient survival. In KIRC, the parameter IL4/IL13 is an independent prognostic factor for RFS and OS [ 29 , 30 ]. EREG plays a carcinogenic role by binding to EGFR in various human tumors, such as colorectal cancer [ 31 , 32 ], nonsmall cell lung cancer [ 33 – 35 ], and gliomas [ 36 ].…”

Re-Evaluating the Effects of Obesity on Cancer Immunotherapy Outcomes in Renal Cancer: What Do We Really Know?

“…Khojandi et al found no significant associations (positive or negative) between either BMI or plasma leptin concentrations and PD-1 expression on peripheral blood CD8+ T cells in a cohort of 27 melanoma patients, 11 breast cancer patients, and 30 non-Hodgkin lymphoma patients who ranged from having a normal body weight to having obesity ( 30 ). Our own examination of treatment-naive renal cancer patients found that higher plasma leptin concentrations were associated with reduced frequencies of peripheral blood PD-1+CD8+ T cells; in this patient cohort higher BMIs were also associated with reduced frequencies of activated CD45RO+CD8+ T cells ( 31 ). We found that in the renal tumor microenvironment, pro-angiogenic factors VEGF-A and placental growth factor (PLGF) were elevated in subjects with obesity ( 31 ), whereas the frequency of activated PD-1 high CD8+ T cells was reduced ( 18 ) ( Figure 2 ).…”

“…Our own examination of treatment-naive renal cancer patients found that higher plasma leptin concentrations were associated with reduced frequencies of peripheral blood PD-1+CD8+ T cells; in this patient cohort higher BMIs were also associated with reduced frequencies of activated CD45RO+CD8+ T cells ( 31 ). We found that in the renal tumor microenvironment, pro-angiogenic factors VEGF-A and placental growth factor (PLGF) were elevated in subjects with obesity ( 31 ), whereas the frequency of activated PD-1 high CD8+ T cells was reduced ( 18 ) ( Figure 2 ). However, our nanoString analysis of immune-related genes in treatment-naive human renal tumors revealed that of the ~750 genes examined, surprisingly few were altered by obesity ( 31 ).…”

“…We found that in the renal tumor microenvironment, pro-angiogenic factors VEGF-A and placental growth factor (PLGF) were elevated in subjects with obesity ( 31 ), whereas the frequency of activated PD-1 high CD8+ T cells was reduced ( 18 ) ( Figure 2 ). However, our nanoString analysis of immune-related genes in treatment-naive human renal tumors revealed that of the ~750 genes examined, surprisingly few were altered by obesity ( 31 ). Similar conclusions were reached by Sanchez et al, who performed an unbiased transcriptomic analysis of renal tumors from both treatment-naive patients and those treated with tyrosine kinase inhibitors (TKIs) ( 32 ).…”

Treatment strategies for clear cell renal cell carcinoma: Past, present and future

“…Obesity is one of the main risk factors for ccRCC, and the term “obesity” here refers to the “ body mass index (BMI) ≥30 kg/m 2 ” defined by the WHO ( 115 ). Compared with people with normal BMI, people who are overweight (25 kg/m 2 ≤ BMI <30 kg/m 2 ) have a risk ratio of 1.28 for ccRCC, and obese people have a risk ratio of 1.82 ( 116 ).…”