Editors' ChoiceCancer Immunotherapy

Trimming the “fatty” intratumoral Tregs for cancer immunotherapy

See allHide authors and affiliations

Science Translational Medicine  11 Mar 2020:
Vol. 12, Issue 534, eabb2770
DOI: 10.1126/scitranslmed.abb2770


Fatty acid receptor CD36 preferentially regulates intratumoral but not peripheral Tregs.

Cancer immunotherapy has emerged as the fourth pillar of cancer care, in addition to surgery, radiotherapy, and chemotherapy. In recent years, one of the prominent developments in cancer immunotherapy is immune checkpoint blockade therapies (ICBs). By blocking immunosuppressive checkpoints that are enriched in the tumor microenvironment (TME), such as cytotoxic T-lymphocyte-associated protein 4 and programmed cell death 1 (PD-1), ICBs boost antitumor immune responses. One mechanism underlying ICB-elicited immune responses is believed to be through blocking or depleting Foxp3+ regulatory T cells (Tregs). However, Tregs also play an essential role in maintaining peripheral homeostasis. As such, indiscriminate inhibition of Tregs by ICBs can lead to inadvertent autoimmune responses, some of which can be life-threatening, resulting in premature termination of ICBs and limiting their clinical utilization. Thus, targeting modulators specifically associated with intratumoral but not peripheral Tregs could be an attractive approach to enhance antitumor immunity.

Considering that intratumoral Tregs live in a metabolically unique TME, Wang et al. conducted metabolic characterization of intratumoral versus peripheral Tregs collected from both murine and human tumors. They found that intratumoral Tregs exhibited greater lipid metabolism and expression of CD36, a key receptor for fatty acid uptake. Using a genetic mouse model with specific deletion of CD36 in Tregs and blocking antibodies against CD36, the authors showed that loss of function of CD36 selectively impacts intratumoral Tregs, evidenced by reduced frequency and impaired suppressive function. Consequently, tumor-infiltrating T cells possessed greater effector function with augmented production of interferon-γ (IFN-γ) and tumor necrosis factor–α (TNF-α), two crucial effector molecules in antitumor immunity. Importantly, the peripheral Treg compartment in the spleen remained intact, supported by normal gross histopathology of multiple vital organs and suppression of experimental colitis induction. Mechanistically, the authors revealed that CD36 promotes survival of Tregs, likely by acting on the PPAR-β pathway to modulate mitochondrial fitness and intracellular level of nicotinamide adenine dinucleotide, which is essential for Treg conversion of lactic acid, an abundant metabolite/nutrient in TME. Taken together, targeting CD36 represents a promising approach to specifically impair intratumoral Tregs without disrupting peripheral immune homeostasis, which in conjunction with anti–PD-1 induces encouraging therapeutic effects in tumor-bearing mice.

Notwithstanding novel insights gained from this study, some points need to be clarified. Does the lack of CD36 affect the trafficking of Tregs into the tumor? Do CD36−/− Foxp3+ cells lose their Treg identity and become more effector T cell–like, producing cytokines such as IFN-γ and TNF-α? How would blocking CD36 in patients affect other cell types? Although there is still work to be done, these results highlight a potential way to specifically target intratumoral Tregs.

Highlighted Article

Stay Connected to Science Translational Medicine

Navigate This Article