The adaptive immune system is a major driver of selection for tumor suppressor gene inactivation

• Published in: Science (American Association for the Advancement of Science) Vol. 373; no. 6561; pp. 1327 - 1335
• Main Authors: Martin, Timothy D., Patel, Rupesh S., Cook, Danielle R., Choi, Mei Yuk, Patil, Ajinkya, Liang, Anthony C., Li, Mamie Z., Haigis, Kevin M., Elledge, Stephen J.
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 17.09.2021
• Subjects: Adaptive systems; Animal models; Animals; Antigen presentation; Antigen processing; Antigens; Cancer; Carcinogenesis; Cell culture; Cell Line, Tumor; Chemokine CCL2 - metabolism; Clonal selection; CRISPR; CRISPR-Cas Systems; Evolution; Female; Gene expression; Gene Silencing; Genes; Genes, Tumor Suppressor; GTP-Binding Protein alpha Subunits, G12-G13 - genetics; GTP-Binding Protein alpha Subunits, G12-G13 - metabolism; Humans; Immune checkpoint; Immune Evasion - genetics; Immune system; Inactivation; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - immunology; Mammary Neoplasms, Experimental - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, SCID; Mutation; Neoplasm Transplantation; Neoplasms, Experimental - genetics; Neoplasms, Experimental - immunology; Neoplasms, Experimental - pathology; Pancreatic cancer; Selection, Genetic; Tumor cell lines; Tumor Microenvironment; Tumor suppressor genes; Tumorigenesis; Tumors
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abg5784

Mouse models used to study cancer often lack a full immune system, allowing implantation of human tumors into the mice. By contrast, naturally evolving tumors must contend with a fully functional immune system and its destruction of some of the cells (see the Perspective by Ho and Wood). Two groups now report studies on mouse models with a fully intact immune system. Martin et al . started with preexisting murine tumor cell lines and examined their continued evolution in vivo, whereas Del Poggetto et al . examined the development of new pancreatic tumors in the context of inflammation, as is often seen in human patients. In each study, the authors found that the immune system exerted a selective pressure on cells that would give rise to tumors, promoting the survival of those that had lost expression of tumor suppressor genes or activated a specific oncogene. The findings suggest a major role for the immune system in driving tumor evolution across multiple types of cancer. —YN Immune selection pressure in developing tumors favors inactivation of tumor suppressor genes. During tumorigenesis, tumors must evolve to evade the immune system and do so by disrupting the genes involved in antigen processing and presentation or up-regulating inhibitory immune checkpoint genes. We performed in vivo CRISPR screens in syngeneic mouse tumor models to examine requirements for tumorigenesis both with and without adaptive immune selective pressure. In each tumor type tested, we found a marked enrichment for the loss of tumor suppressor genes (TSGs) in the presence of an adaptive immune system relative to immunocompromised mice. Nearly one-third of TSGs showed preferential enrichment, often in a cancer- and tissue-specific manner. These results suggest that clonal selection of recurrent mutations found in cancer is driven largely by the tumor’s requirement to avoid the adaptive immune system.