Oxidized Lipoproteins Promote Resistance to Cancer Immunotherapy Independent of Patient Obesity

Abstract

Antitumor immunity is impaired in obese mice. Mechanistic insight into this observation remains sparse and whether it is recapitulated in patients with cancer is unclear because clinical studies have produced conflicting and controversial findings. We addressed this by analyzing data from patients with a diverse array of cancer types. We found that survival after immunotherapy was not accurately predicted by body mass index or serum leptin concentrations. However, oxidized low-density lipoprotein (ox-LDL) in serum was identified as a suppressor of T-cell function and a driver of tumor cytoprotection mediated by heme oxygenase-1 (HO-1). Analysis of a human melanoma gene expression database showed a clear association between higher HMOX1 (HO-1) expression and reduced progression-free survival. Our in vivo experiments using mouse models of both melanoma and breast cancer revealed HO-1 as a mechanism of resistance to anti-PD1 immunotherapy but also exposed HO-1 as a vulnerability that could be exploited therapeutically using a small-molecule inhibitor. In conclusion, our clinical data have implicated serum ox-LDL as a mediator of therapeutic resistance in patients with cancer, operating as a double-edged sword that both suppressed T-cell immunity and simultaneously induced HO-1–mediated tumor cell protection. Our studies also highlight the therapeutic potential of targeting HO-1 during immunotherapy, encouraging further translational development of this combination approach. See article by Kuehm et al., p. 227

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

“…In contrast, the melanoma tumors examined did not display this relationship. Finally, our analysis of CD8+ TILs from renal cancer patients showed that obesity is associated with reduced frequencies of PD-1 high CD8+ TILs ( 18 ), which differs from the lack of an association between obesity and PD-1+CD8+ TILs found in a combined cohort of melanoma and breast cancer patients ( 30 ). Collectively, these findings illustrate that immune responses to solid tumors can vary greatly between tumor types.…”

“…Two recent studies did not observe positive associations between leptin concentration and the frequency of PD-1+CD8+ T cells. 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 ).…”

“…This relationship was particularly strong for women (HR for PFS = 2.06; 95% CI [1.06-3.98]; p = 0.032) but not men (HR for PFS = 1.40; 95% CI [0.59-3.31]; p = 0.45) ( 39 ). The 2021 study by Khojandi et al found that in a cohort of 129 melanoma patients treated with anti-CTLA-4 (ipilimumab) a BMI ≥ 30kg/m 2 at treatment initiation was associated with better OS (p = 0.0368) ( Table 1 ) but had no effect on PFS ( 30 ). However, the same authors found that in a cohort of 149 patients with melanoma or other tumor types who were treated with anti-PD-1 (nivolumab or pembrolizumab) or anti-PD-L1 (atezolizumab or durvalumab), obesity defined by BMI had no effect on OS (p = 0.7003) ( Table 2 ), reflecting the findings of Young et al ( 42 ) In looking further at these disparate results, Khojandi et al found that the relative amount of oxidized low density lipoproteins (ox-LDL) in circulation predicted anti-PD-1 or PD-L1 outcomes, with high ox-LDL being associated with poor OS, due to the ability of ox-LDL to activate the cytoprotective molecule hemeoxygenase -1 (HO-1) in tumor cells, which made them less susceptible to T cell-mediated killing ( 30 ).…”

“…The 2021 study by Khojandi et al found that in a cohort of 129 melanoma patients treated with anti-CTLA-4 (ipilimumab) a BMI ≥ 30kg/m 2 at treatment initiation was associated with better OS (p = 0.0368) ( Table 1 ) but had no effect on PFS ( 30 ). However, the same authors found that in a cohort of 149 patients with melanoma or other tumor types who were treated with anti-PD-1 (nivolumab or pembrolizumab) or anti-PD-L1 (atezolizumab or durvalumab), obesity defined by BMI had no effect on OS (p = 0.7003) ( Table 2 ), reflecting the findings of Young et al ( 42 ) In looking further at these disparate results, Khojandi et al found that the relative amount of oxidized low density lipoproteins (ox-LDL) in circulation predicted anti-PD-1 or PD-L1 outcomes, with high ox-LDL being associated with poor OS, due to the ability of ox-LDL to activate the cytoprotective molecule hemeoxygenase -1 (HO-1) in tumor cells, which made them less susceptible to T cell-mediated killing ( 30 ). In support of the above findings that counter the obesity paradox paradigm, Rutkowski et al reported that BMI had no effect on OS in a cohort of 688 metastatic melanoma patients receiving first line ICI (HR = 1.02; 95% CI [0.99-1.05]; p = 0.202) or ICI sequencing (HR 1.02; 95% CI [0.99-1.04]; p = 0.237) in Italy and Poland ( 41 ) ( Table 2 ) and Di Filippo et al found that BMI status did not predict PFS (p = 0.88) or OS (p = 0.25) in a cohort of 1214 melanoma patients treated with first line ICI or targeted therapies in the French 26-center prospective MelBase study ( 43 ) ( Table 2 ).…”

Renal cell carcinoma (RCC): fatter is better? A review on the role of obesity in RCC

“…The PD1-mediated T cell dysfunction in obesity could explain better outcomes for patients with obesity treated with ICIs (Wang et al 2019). However, these results were not confirmed by Khojandi et al that found no associations between BMI, leptin levels and PD1 expression on CD8 + tumorinfiltrating lymphocytes in a mixed cohort of melanoma and breast cancer patients (Khojandi et al 2021).…”