IFNγ-producing NK cells induced TME remodeling and orchestrated T cell–mediated tumor control.

  • Major Finding: IFNγ-producing NK cells induced TME remodeling and orchestrated T cell–mediated tumor control.

  • Concept: Prostaglandin E2 could bind EP2 and EP4 on natural killer cells, blocking this microenvironment change.

  • Impact: The inflammatory phenotypes in mouse tumors were seen in human tumors, with prognostic relevance.

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Immunologically “hot” T cell–inflamed tumors that are substantially infiltrated by cytotoxic T cells often respond better to immunotherapy than their “cold” counterparts, but the steps leading to high T-cell infiltration and effector function in these tumors are not completely understood. Bonavita and colleagues extensively characterized the tumor microenvironments (TME) of highly T cell–inflamed tumors, the growth of which is restricted by the immune system in mice. This analysis revealed that immune control of cyclooxygenase (COX) enzyme–deficient tumors, which are depleted of the inflammation-associated downstream COX product prostaglandin E2 (PGE2), depended on infiltration by natural killer (NK) cells that produce IFNγ. These NK cells not only killed tumor cells effectively on their own, but also caused TME remodeling that led to accumulation of cytotoxic T cells that restricted tumor growth. The effects of PGE2 in these tumors were determined to be mediated by binding of PGE2 to the G protein–coupled receptors EP2 and EP4 on NK cells, preventing NK cell–induced TME alterations, allowing tumors to circumvent immune control. Highlighting the potential clinical relevance of these findings, an investigation of patient datasets representing a variety of cancer types, including patients receiving immune checkpoint blockade (ICB) therapies, demonstrated that the types of protumorigenic and antitumorigenic TME inflammatory profiles observed in mice were also present in human tumors and were prognostically significant and predicted response and survival with ICB. Together, these results reveal previously unknown mechanisms by which inflammation-associated tumor characteristics relate to immune control of tumors, with clear implications for ICB efficacy.

Bonavita E, Bromley CP, Jonsson G, Pelly VS, Sahoo S, Walwyn-Brown K, et al. Antagonistic inflammatory phenotypes dictate tumor fate and response to immune checkpoint blockade. Immunity 2020;53:1215–29.E8.

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