Checkpoint blockade
immunotherapy relies on the empowerment of the immune system to fight
cancer. Why some patients fail to achieve durable clinical responses is not well understood, but unique individual factors such as diet,
obesity, and related
metabolic syndrome could play a role. The link between
obesity and patient outcomes remains controversial and has been mired by conflicting reports and limited mechanistic insight. We addressed this in a C57BL/6 mouse model of diet-induced
obesity using a Western diet high in both
fats and
sugars. Obese mice bearing
B16 melanoma or MC38
carcinoma tumors had impaired immune responses to
immunotherapy and a reduced capacity to control
tumor progression. Unexpectedly, these compromised therapeutic outcomes were independent of body mass and, instead, were directly attributed to dietary
fructose.
Melanoma tumors in mice on the high-
fructose diet were resistant to
immunotherapy and showed increased expression of the cytoprotective
enzyme heme oxygenase-1 (HO-1). This increase in HO-1
protein was recapitulated in human A375
melanoma cells exposed to
fructose in culture. Induced expression of HO-1 shielded
tumor cells from immune-mediated killing and was critical for resistance to checkpoint blockade
immunotherapy, which could be overcome in vivo using a small-molecule inhibitor of HO-1. This study reveals dietary
fructose as a driver of tumor immune evasion, identifying HO-1 expression as a mechanism of resistance and a promising molecular target for combination
cancer immunotherapy.See article by Khojandi et al., p. 214.