Immunotherapy has emerged as an effective means to restore immune recognition of cancer. Numerous forms of immunotherapy are currently being explored clinically. The most common are vaccines (dendritic cell, viral, and whole tumor cell based), adoptive T cell therapy and immune checkpoint blockade. The recent successes in melanoma, renal cancer, and lung cancer have generated renewed optimism for treatment of multiple cancer types that were believed not amenable to immune-based therapies. However, immune-related events such as colitis, dermatitis, and, less frequently, endocrinopathy and pneumonitis have been reported and can be a challenge in the clinical use of these approaches. Cytokine release syndrome has been reported in the case of CAR (chimeric antigen receptor) T cell therapy and treatment with agonist antibodies. In this issue, Mirsoian et al. provide evidence that adiposity in aged mice induces a lethal cytokine storm following systemic administration of stimulatory immunotherapy consisting of anti-CD40 agonist antibody with IL-2.

This is an elegant follow up to a previous study by the same authors in which they showed that systemic immunotherapy administration in aged mice resulted in the induction of a rapid and lethal cytokine storm. In the current paper, they find that it is the fat that accumulates during aging, and mainly the visceral fat, that is associated with toxicity. This results in increased levels of proinflammatory M1 macrophages within the peritoneal cavity and visceral adipose tissues, leading to heightened production of TNF. In order to confirm that it is indeed the fat that is associated with lethal effects, the authors repeated their studies in young mice with genetic (ob/ob) or diet-induced obesity (DIO). While young obese mice also displayed severe toxicity to the therapy, it was much more severe in older mice suggesting that age is also a significant factor. Reciprocally, calorie-restricted aged mice had lower visceral body fat content and reduced cytokine levels, with increased survival following immunotherapy. Obese mice were also protected by macrophage depletion or TNF blockade. These data demonstrate the need to consider age and body fat content as variables in preclinical assessment of therapeutics and when modeling diseases such as cancer.

Since many cancer patients fall into the elderly category, this study brings up a critical point that aged mice respond differently to immunotherapy than younger mice. This also highlights an important issue when considering potential toxicities associated with any therapy, as most animal studies are performed in young, healthy mice. Another interesting point is the potential impact of body mass index and adipose accumulation in predicting side effects when investigating and utilizing immunotherapies. This is a very important and impactful finding for the field, and further investigations in tumor bearing mice with commonly used therapies are warranted. If the findings are confirmed in other therapeutic settings, the inclusion of supportive measures, such as TNF blockade, should continue to be considered for early management of immune-related toxicities to improve clinical outcomes.

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J. Exp. Med.