Abstract
Low intratumor heterogeneity correlates with increased patient survival and immunotherapy response. However, even highly homogeneous tumors are vari-ably aggressive, and the immunologic factors impacting aggressiveness remain understudied. In this study, we analyzed the mechanisms underlying immune escape in murine tumors with low intratumor heterogeneity. We used immunophenotyping and single-cell RNA sequencing to compare the temporal growth of in vivo transplanted, genetically similar, rejected and nonrejected single-cell clones. Nonrejected clones showed high infiltration of tumor-associated macrophages, lower T cell infiltra-tion, and increased T cell exhaustion when compared with rejected clones. Comparative analysis of rejection-associated gene expression programs, combined with in vivo CRISPR knockout screens of candidate regulators, identified macrophage migration inhibitory factor (Mif) as a major con-tributor to preventing immune rejection. Mif knockout resulted in smaller tumors and reduced tumor-associated macrophage infiltration. These results were validated in patients with melanoma. Overall, our homogeneous tumor system can uncover factors regulating growth variability and identifies Mif as critical in aggressive melanoma. Significance: In this study, we find that Mif expression is associated with tumor growth and aggressiveness, specifically in tumors with low heterogeneity. These findings could facilitate the development of new strategies to treat patients with homogeneous, high MIF–expressing tumors that are unresponsive to immune checkpoint therapy.
| Original language | English |
|---|---|
| Pages (from-to) | 553-577 |
| Number of pages | 25 |
| Journal | Cancer Discovery |
| Volume | 15 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 1 Mar 2025 |
Funding
Y. Samuels is supported by the Israel Science Foundation grant number 2133/23, the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement number 770854), and the European Union (European Research Council, Mel-Immune, 101094980). This research was further supported by the Center for Immunotherapy at the Weizmann Institute of Science, the MRA (917324), the Minerva Stiftung with the funds from the BMBF of the Federal Republic of Germany , the ICRF (20-802-ICG), the Alisa and Peter Savitz Foundation, Les and Cyndy Lederer, Brenda Gruss and Daniel Hirsch, the Donald Gordon Foundation, the Sigmund and Sofie Englander Foundation, Ted and Sylvia Quint 78775, Margaret and Leo Meyer and Hans M. Hirsch Foundation 77888, Estate of Rena G. Moses 111677, Samowitz Foundation Trust 74163, the Dwek Institute for Cancer Therapy Research, the Estate of Gerald Alexander, the Estate of Jackson Toby, and the Estate of Gertrude Buchler, as well as Laboratory in the name of M.E.H Fund established by Margot and Ernst Hamburger. This research was supported in part by the Intramural Research Program of the NIH, NCI. Y. Samuels is the incumbent of the Knell Family Professorial Chair. Y. Samuels is the Director of the Moross Integrated Cancer Center. A.T. Satpathy was supported by a Career Award for Medical Scientists from the Burroughs Wellcome Fund, a Lloyd J. Old STAR Award from the Cancer Research Institute, a Pew-Stewart Scholars for Cancer Research Award, and the Parker Institute for Cancer Immunotherapy. The images in this article were acquired at the Advanced Optical Imaging Unit, de Picciotto-Lesser Cell Observatory unit at the Moross Integrated Cancer Center, Life Science Core Facilities, Weizmann Institute of Science. This work used the computational resources of the NIH HPC Biowulf Cluster (http://hpc.nih.gov). J.A. Pai was supported by NIH Training Grant 5T32AI007290.
All Science Journal Classification (ASJC) codes
- Oncology