While Obesity Drives Cancer Growth, It May Make Checkpoint Inhibitors More Effective

While obesity is a risk factor for cancer and can promote cancer growth and recurrence, research published this week has found that, paradoxically, obesity can make checkpoint inhibitors more effective in treating cancer.

Although obesity—or a body mass index of 30 or greater—is characterized by inflammation and dysregulated immune responses, little is known about the impact of obesity on immune responses during cancer therapy. The newly published study sought to investigate the impact of obesity on the programed death ligand 1 (PD-L1) axis, immune aging, and dysfunction.

In a mouse model, the researchers found that, in obese mice, there was a significant increase in PD-1 expression and decreased proliferative function versus nonobese mice. In tumor-bearing obese mice, T cells exhibited a transcriptomic profile that was markedly different from that of T cells in tumor-bearing control mice, which the authors say is consistent with a state of increased exhaustion and inflammation.

Furthermore, the authors found that levels of the weight-regulating hormone leptin—which are elevated in the metainflammatory state of obesity—are correlated with PD-1 expression. While leptin has previously been suspected to affect T cell function, the current research found that, in obese mice, there were marked changes in the expression of genes involved with leptin signaling. Weight reduction of the obese mice resulted in lower leptin and a lower frequency of PD-1+ CD8+ T cells.

Building on the understanding that CD8+ T cells have increased dysfunction in obese mice, the researchers assessed the impact of a PD-1 blockade on tumor growth. Using an anti—PD-1 agent as monotherapy had little to no effect on the control mice, but led to a reduction in tumor burden and significant improvement in obese mice.

While tumor growth was faster in obese mice, these mice showed “significantly greater therapeutic efficacy than control recipients.” This fact was due, write the researchers, to an increase in the number of tumor-infiltrating T cells and the increased presence of CD8+ T cells.

“It's counterintuitive because up to this point all of our studies showed that obesity resulted in more toxicities associated with immunotherapy treatments,” said William J. Murphy, PhD, a coauthor of the study and vice chair of research in the University of California Davis department of dermatology, in a statement. “This is a game-changer because when we personalize medicine and look at body mass index, in some situations it can be bad, and in some situations it can be helpful.”

However, caution the authors, “Obesity should not necessarily be regarded as a positive prognostic factor in cancer but rather as a potential mediator of immune dysfunction and tumor progression that can be successfully reversed by PD-L1 checkpoint inhibition resulting in heightened efficacy.”

Reference

Wang Z, Aguilar EG, Luna JI, et al. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade [published online November 12, 2018]. Nat Med. doi: 10.1038/s41591-018-0221-5.