Bowen Dong

Obesity increases cancer incidence and aggressiveness but is paradoxically associated with improved response to immunotherapy. Here, we show that intratumoral levels of leptin (LEP), a factor contributing to the development of obesity, predict improved outcomes of breast and liver cancers. In contrast, these levels of LEP are associated with poor survival of patients with colon and esophageal cancers, where they are uniquely correlated with high IDO1 levels in tumor-associated myeloid cells. LEP-exposed human macrophages show elevated levels of multiple T cell–activating factors but also show NF-κB– and STAT3-dependent IDO1 induction, which synergize with IFN-γ in activating the kynurenine pathway, resulting in their T cell–suppressive function. IDO1 inhibition reprograms the LEP-exposed macrophages from metabolic suppression to enhanced T cell–stimulatory function. The double-edged impact of LEP on human myeloid cells helps explain obesity-associated immune dysfunction and the “obesity paradox,” suggesting that IDO1 inhibition may be selectively beneficial in patients who have obesity and cancer with high levels of LEP.

Human peripheral blood CD8+ T cells require NKR-mediated co-stimulation for optimal effector response to weak TCR stimulation.

NKRs assist CTLs to recognize and conjugate cancer cells expressing low-level MHCI/peptide complexes.

DNAM-1 and NKG2D expression is correlated with long term survival and cytotoxic genes in tumor samples from melanoma patients (TCGA).

Expression of DNAM-1 and DNAM-1-competing (inhibitory) receptors reflects CTL cytotoxic function.

DNAM-1 signaling assists TCR signaling in CTLs.

Chemotherapeutic drugs elevate NKR-L expression on cancer cells.

DC-primed MART-1-specific CTLs express high levels of NKRs, but recognize and kill cancer cells in a strictly TCR-dependent manner.

DC-primed MART-1-specific CTLs express high levels of NKRs, but recognize and kill cancer cells in a strictly TCR-dependent manner.

DNAM-1 and NKG2D expression is correlated with long term survival and cytotoxic genes in tumor samples from melanoma patients (TCGA).