The adaptive immune system selects for inactivation of tumor suppressor genes in multiple cancer models.

  • Major Finding: The adaptive immune system selects for inactivation of tumor suppressor genes in multiple cancer models.

  • Concept: CRISPR screens in immunocompetent and immunocompromised mice identified genes whose loss supports immune evasion.

  • Impact: This work suggests recurrent cancer mutations are driven by evasion of the adaptive immune response.

Throughout tumorigenesis, cancer cells go through many adaptive processes, one of which involves evading immune surveillance. Numerous genes have been found to be mutated to enhance this immune escape phenotype and include those involved in antigen presentation as well as oncogenic drivers such as KRAS and MYC. However, the spectrum of genes that conversely promote immune recognition as well as their role within cancer are not as widely regarded, and in vitro genetic screens for cancer phenotypes fail to account for the selective pressure of the immune system. Martin, Patel, and colleagues performed CRISPR screens in murine tumor cells implanted into either immunocompetent or immunocompromised mice to identify overlap of genes needed for adaptive immune system recognition and those whose human counterparts were most frequently mutated in cancers. Tumor suppressor genes (TSG) were among those most enriched in wild-type mice as compared with immunocompromised mice in breast and colon cancer models, suggesting that the adaptive immune system is selecting for the inactivation of TSGs during tumor progression. Three of the top-scoring genes were Gna13, Cul3, and Hdac2, which have unknown roles in regulating tumor cell response to the adaptive immune system. Using a CRISPR library, sgRNAs against Gna13, Cul3, or Hdac2 were used and an adaptive immune system–specific tumor suppressor phenotype was confirmed for all. Knockout of these genes did not alter antigen presentation, however, suggesting that the role of these genes is outside of CD8 T cell–mediated killing. Further analysis of RNA-sequencing data indicated that the chemokine gene Ccl2 was overexpressed upon Gna13 loss and subsequently immune suppressive M2 macrophages were also enriched in tumors lacking GNA13 expression. Alterations to tumor growth through this mechanism were only observed in wild-type mice, further suggesting the need for the adaptive immune system to suppress tumor growth. This study implicates a large number of tumor suppressors in the promotion of immune evasion, leading to a greater understanding of tumor biology.

Martin TD, Patel RS, Cook DR, Choi MY, Patil A, Liang AC, et al. The adaptive immune system is a major driver of selection for tumor suppressor gene inactivation. Science 2021;373:1327–35.

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