Tumor immune evasion arises through loss of TNF sensitivity

Abstract

Immunotherapy has revolutionized outcomes for cancer patients, but the mechanisms of resistance remain poorly defined. We used a series of whole-genome clustered regularly interspaced short palindromic repeat (CRISPR)-based screens performed in vitro and in vivo to identify mechanisms of tumor immune evasion from cytotoxic lymphocytes [CD8 T cells and natural killer (NK) cells]. Deletion of key genes within the tumor necrosis factor (TNF) signaling, interferon-γ (IFN-γ) signaling, and antigen presentation pathways provided protection of tumor cells from CD8 T cell-mediated killing and blunted antitumor immune responses in vivo. Deletion of a number of genes in the TNF pathway also emerged as the key mechanism of immune evasion from primary NK cells. Our screens also identified that the metabolic protein 2-aminoethanethiol dioxygenase (Ado) modulates sensitivity to TNF-mediated killing by cytotoxic lymphocytes and is required for optimal control of tumors in vivo. Remarkably, we found that tumors delete the same genes when exposed to perforin-deficient CD8 T cells, demonstrating that the dominant immune evasion strategy used by tumor cells is acquired resistance to T cell-derived cytokine-mediated antitumor effects. We demonstrate that TNF-mediated bystander killing is a potent T cell effector mechanism capable of killing antigen-negative tumor cells. In addition to highlighting the importance of TNF in CD8 T cell- and NK cell-mediated killing of tumor cells, our study also provides a comprehensive picture of the roles of the TNF, IFN, and antigen presentation pathways in immune-mediated tumor surveillance.

Future Therapeutic Directions for Smac-Mimetics

“…An alternative option to amplifying the immune response, is to reduce the threshold of a tumor cell to respond to immunotherapy. Using a CRISPR/Cas9 screen, Kearney et al 2018, showed that the suppression of TNF, Interferon (IFNγ) and antigen presentation were key mechanisms by which tumors can evade the attack of CLs [151]. This matched well with previous clinical data showing that IFNγ plays an important role in the efficacy of ICIs [152], but for the first time suggested TNF signaling was also an important component.…”

Cancer outcomes in patients requiring immunosuppression in addition to corticosteroids for immune‐related adverse events after immune checkpoint inhibitor therapy

“…With regard to understanding the role of TNF to both immune‐mediated anticancer activity and irAEs, preclinical data are conflicting. For example, a significant preclinical role for TNF in the killing of tumor cells by both CD8 + cytotoxic T lymphocytes and natural killer cells has been uncovered recently . In contrast, Liu et al.…”

Whole exome precision oncology targeting synthetic lethal vulnerabilities across the tumor transcriptome

“…(2) Instead of using the genome-scale functional screens in cancer cell lines (DepMap 12,13 ) in the first step of ISLE or INCISOR, we analyze genome-wide CRISPR screens performed in co-cultures of cancer and T-cells, identifying genes whose knock-out enhances or prevents T-cell mediated killing. To this end we incorporated four such genome-wide CRISPR screens publicly available [51][52][53][54] . Since two of them involve treatment of anti-PD1/PDL1, we used these two as the basis for identifying GIs involved in anti-PD1 response prediction 52,54 ; whereas the remaining two screens, identifying those genes involved in generic immune response 51,53 , were used to infer GIs for anti-CTLA4 response prediction.…”

“…To this end we incorporated four such genome-wide CRISPR screens publicly available [51][52][53][54] . Since two of them involve treatment of anti-PD1/PDL1, we used these two as the basis for identifying GIs involved in anti-PD1 response prediction 52,54 ; whereas the remaining two screens, identifying those genes involved in generic immune response 51,53 , were used to infer GIs for anti-CTLA4 response prediction. (3) We focused on the mediators of resistance to immune checkpoint therapies using synthetic rescue (SR) interactions, as no statistically significant SL interaction partners were identified via ISLE for either PD1 or CTLA4.…”