Identification of essential genes for cancer immunotherapy

Abstract

Somatic gene mutations can alter the vulnerability of cancer cells to T cell-based immunotherapies. To mimic loss-of-function mutations involved in resistance to these therapies, we perturbed genes in tumour cells using a genome-scale CRISPR-Cas9 library comprising ~123,000 single guide RNAs, and profiled genes whose loss in tumour cells impaired the effector function of CD8+ T cells (EFT). We correlated these genes with cytolytic activity in ~11,000 patient tumours from The Cancer Genome Atlas. Among the genes validated using different cancer cell lines and antigens, we identified multiple loss-of-function mutations in APLNR, encoding Apelin receptor, in patient tumours refractory to immunotherapy. We show that APLNR interacts with JAK1, modulating interferon-gamma responses in tumours, and its functional loss reduces the efficacy of adoptive cell transfer and checkpoint blockade immunotherapies in murine models. Collectively, our study links the loss of essential genes for EFT with the resistance or non-responsiveness of cancer to immunotherapies.

Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead

“…Breakthrough discoveries will be necessary to be able to consistently elevate a patient's cancer immune set point and to recover MHC class I antigens in those tumors that downregulate them. One recent study with large therapeutic and prognostic implications used the new CRISPR technique to reveal multiple mutations in the tumor genes of individual patients who failed immunotherapy [96] . Some of these identified genes may be associated with loss of tumor antigen expression, while others may involve disturbances in tumor cytokine production or T-cell co-stimulation.…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…[105][106][107][108][109][110] Accordingly, RCD can no longer be perceived as immunogenic when: (1) the intracellular stress responses regulating the emission of ICD-associated DAMPs are pharmacologically or genetically ablated in cancer cells; or (2) when the molecular machinery dedicated to DAMP detection is inhibited or ablated. 13,44,84,91,93,97 Moreover, ICD-driven immunity can no longer operate in the presence of general immunological defects, 111 such as (1) an intrinsically low antigenicity of cancer cells, owing to low levels of TAAs or downregulation of MHC Class I molecules [112][113][114][115][116][117][118][119] ; (2) an increased immunological tolerance of the host, secondary to increased amounts of immunosuppressive cytokines, [120][121][122][123][124][125][126][127][128] or inhibitors of chemotaxis, [129][130][131][132][133][134] increased tumor infiltration by immunosuppressive cell populations, [135][136][137][138][139][140]…”

Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types

“…Innate or acquired resistance to therapies targeting PD-1/PD-L1 has been shown to be most prevalent in patients with poor PD-L1 expression in the TME as well as those harboring defects in IFN-γ signaling and antigen processing and presentation pathways. 8–11 HDAC inhibitors enhance these factors. First, we show in this study that HDAC inhibition enhances PD-L1 expression on human carcinoma cells in vitro and in vivo (Table 1, Figure 1).…”

“…1,6 In addition, previous research, mostly in melanoma and non-small cell lung (NSCL) cancer, strongly suggests that resistance to checkpoint blockade, including targeting the PD-1/PD-L1 axis, is highly associated with innate or acquired tumor defects in interferon (IFN)‒γ signaling and antigen processing and presentation pathways. 7–11 …”