Journal
JOURNAL OF HEMATOLOGY & ONCOLOGY
Volume 15, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13045-022-01389-y
Keywords
CRISPR screen; Immunotherapy; Cancer immunology; Genetic interaction; Double knockout; Systems biology
Categories
Funding
- Yale SBI/Genetics Startup Fund
- NIH/NCI/NIDA [DP2CA238295, 1R01CA231112, U54CA209992-8697, R33CA225498, RF1DA048811]
- DoD [W81XWH-17-1-0235]
- Damon Runyon Dale Frey Award [DFS-13-15]
- Melanoma Research Alliance [412806, 16-003524]
- St-Baldrick's Foundation [426685]
- Breast Cancer Alliance
- Cancer Research Institute (CLIP)
- AACR [499395, 17-20-01-CHEN]
- Mary Kay Foundation [017-81]
- V Foundation [V2017-022]
- Ludwig Family Foundation
- Blavatnik Family Foundation
- Sontag Foundation (DSA)
- Chenevert Family Foundation
- ACGT
- PSSCRA
- Yale Cancer Center (Team Science Award)
- Yale MSTP training grant from NIH [T32GM007205, T32GM007499]
- Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship [F31CA236453]
Ask authors/readers for more resources
Immunotherapy has revolutionized cancer treatments, but resistance remains a major challenge. This study investigates the genetic interactions between significantly mutated tumor suppressors and immune resistance genes in cancer cells' response to T cell killing. The findings provide insights into potential strategies for targeting clinically relevant cancer mutations using existing agents. The study also presents a technology platform and a double knockout library for studying genetic interactions between cancer mutations and immune resistance pathways.
Immunotherapy has transformed cancer treatments; however, a large fraction of patients encounter resistance. Such resistance is mediated by complex factors, often involving interactions between multiple genes. Thus, it is crucially important to identify genetic interactions between genes that are significantly mutated in cancer patients and those involved in immune responses, ideally the ones that currently have chemical compounds for direct targeting. To systematically interrogate such genetic interactions that mediate cancer cells' response to T cell killing, we designed an asymmetric dual perturbation library targeting the matched combinations between significantly mutated tumor suppressors and immune resistance genes. We performed a combinatorial double knockout screen on 1159 gene pairs and identified those where joint loss-of-function renders altered cellular response to T cell cytotoxicity. We also performed comparative transcriptomics-based analyses on tumor and normal samples from TCGA and GTEx cohorts, mutational profiling analyses, and survival analyses to further characterize the significance of identified hits in clinical patients. Interactions between significantly mutated tumor suppressors and potentially druggable immune resistance genes may offer insights on potential new concepts of how to target clinically relevant cancer mutations with currently available agents. This study also provides a technology platform and an asymmetric double knockout library for interrogating genetic interactions between cancer mutations and immune resistance pathways under various settings.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available