Keenan and Qiao et al. showed in mouse models of colorectal liver metastases (CRLMs, which are CTLA-4high) that anti-CTLA-4 (but not anti-PD-1) treatment controlled LIGHT-overexpressing CRLMs by generating systemic and intratumoral immune activation. scRNAseq, CyTOF, and flow cytometry showed that the LIGHT/anti-CTLA-4 combination remodeled the TME; promoted TIL migration into metastases, TLS development, activation and effector functions of T cells and DC maturation; decreased T cell exhaustion; depleted suppressive myeloid cells; and reduced Treg functionality, with some corresponding data in human CRC.
Contributed by Paula Hochman
ABSTRACT: Colorectal cancer and liver metastases are a leading cause of cancer-related mortality. Overexpression of the immunostimulatory cytokine TNFSF14/LIGHT associates with improved survival and correlates with increased tumor-infiltrating lymphocytes in patients and a clinically relevant model of colorectal liver metastases. We demonstrate that LIGHT monotherapy activates T cells, but also induces T cell exhaustion and the recruitment of immunosuppressive elements. As colorectal liver metastases exhibit high levels of CTLA-4 expression, we combined LIGHT overexpression with anti-CTLA-4, leading to complete tumor control. The combination functions by homing tumor-infiltrating lymphocytes, inducing tumor antigen-specific T cells, and reversing T cell exhaustion. Whereas both LIGHT overexpression and anti-CTLA-4 increase tumor-promoting macrophages, the combination eliminates this population. The ability of LIGHT overexpression combined with CTLA-4 inhibition to reverse T cell exhaustion and myeloid cell suppression is supported by analysis of complementary patient cohorts and has strong clinical relevance, especially given that liver metastases contribute to immunotherapy resistance across various cancer types.
Author Info: (1) Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (2) Department of Surgery, Division of Surgical
Author Info: (1) Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (2) Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (3) Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. (4) Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. (5) Departments of Otolaryngology-Head and Neck Surgery and Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. (6) Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (7) Department of Microbiology & Immunology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. (8) Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (9) Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (10) Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. (11) Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (12) Departments of Otolaryngology-Head and Neck Surgery and Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. (13) Department of Microbiology & Immunology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. (14) Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
