Abstract 978: Tim-4+ tissue-resident macrophages impair antitumor T-cell immunity

Abstract

Over 600,000 Americans and 8 million worldwide die of cancer each year. The success of immune checkpoint blockade with anti-PD-1 therapy has been a remarkable clinical advance. However, most patients do not respond to anti-PD-1 monotherapy and the majority of those who initially do respond eventually succumb to the disease. There is currently an unmet need to identify therapeutic strategies to overcome resistance and further enhance the efficacy of anti-PD-1 therapy. Tim-4 is a phosphatidylserine (PS) receptor that has been reported to be expressed on myeloid cells. Prior work has demonstrated that Tim-4 deficiency or blockade in mice is associated with features of autoimmunity and enhanced anti-tumor immunity. Using flow cytometry, immunohistochemistry, and in vivo biodistribution, we determined that Tim-4 is expressed predominantly on tissue-resident macrophages, such as Kupffer cells, peritoneal macrophages, pleural macrophages, and lymph node macrophages, but not tumor-associated macrophages, in mice and humans. We provide evidence that Tim-4+ macrophages produce high levels of the cytokines TNF-α and TGF-β, which have been linked to T cell dysfunction, and also the TGF-β activating integrin αv (CD51). Antibody blockade of Tim-4 enhances the anti-tumor activity of anti-PD-1 therapy after subcutaneous tumor inoculation of B16 melanoma, CT26 colon carcinoma, and MC38 colon carcinoma. Finally, combined blockade of Tim-4 and PD-1 resulted in substantially more curative responses in a MC38 model of peritoneal carcinomatosis, compared to anti-PD-1 monotherapy. This was associated with enhanced CD8+ T cell infiltration into the peritoneal cavity, increased CD8+ T cell/Foxp3+ regulatory T cell ratio, and reduced expression of the exhaustion marker PD-1. Thus, we show that Tim-4+ tissue-resident macrophages impair anti-tumor T cell immunity and antibody blockade of Tim-4 is a strategy that should be considered for clinical studies in cancers resistant to anti-PD-1 monotherapy. Citation Format: Andrew Chow, Sara Schad, Sai K. Sharma, Sadna Budhu, Aditi Gupta, Corrin Pimentel, Hong Zhong, Jason S. Lewis, John T. Poirier, Jedd D. Wolchok, Charles M. Rudin, Taha Merghoub. Tim-4+ tissue-resident macrophages impair antitumor T-cell immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 978.