Aging, Obesity, and Inflammation: Impact of Pre-existing Inflammatory Profiles on Cancer Immunotherapy Responses and T cell Exhaustion

The use of immunotherapy (IT) in cancer has recently resulted in impressive responses. Yet, their usages, especially those involving cytokine therapies, have also resulted in the induction of severe systemic toxicities often not previously characterized in their preclinical animal studies. The vast majority of murine cancer studies are performed using young, lean, SPF inbred mice yet human cancer is a disease of the aged with majority of patients being over the age of 55 with varying levels of body mass indexes and pre-existing inflammatory profiles from lifelong antigen exposure. Here, we determine the effects of adiposity on systemic immunotherapy tolerance in aged compared to young obese mice. Both young ob/ob and DIO generated pro-inflammatory cytokine levels and organ pathologies comparable to aged ad-libitum mice following immunotherapy, culminating in lethality. Caloric-restricted aged mice contain less visceral fat and displayed reduced cytokine levels, protection from organ pathology, and protection from lethality. Our data demonstrates that accounting for the chronic, low-grade, persistent inflammatory profile that is present within aging and obesity renders effects that have similarly been observed in clinical trials with systemic cytokine therapies. Additionally, our studies sought to determine the consequences of pre-existing inflammatory profiles present within obesity and aging on T cell activation and exhaustion to determine if similar effects would be induced by other immunotherapy regimens, namely checkpoint blockade. We show through protein and gene microarray analyses that both obesity and aging result in an exhaustive phenotype within CD4 T cells. However, aged mice displayed characteristics that correlated with a terminal exhaustion phenotype where as CD4 T cells from obese were only partially exhausted. These important molecular insights provide the potential for increased targeting with checkpoint blockade therapy that could be harnessed to reinvigorate anti-tumor responses. Together, our data demonstrates that it is increasingly imperative for measurement of both efficacy as well as toxicity to be conducted in models of appropriate demographics.