Abstract
To realize the full potential of immunotherapy, it is critical to understand the drivers of tumor infiltration by immune cells. Previous studies have linked immune infiltration with tumor neoantigen levels, but the broad applicability of this concept remains unknown. Here, we find that while this observation is true across cancers characterized by recurrent mutations, it does not hold for cancers driven by recurrent copy number alterations, such as breast and pancreatic tumors. To understand immune invasion in these cancers, we developed an integrative multi-omics framework, identifying the DNA damage response protein ATM as a driver of cytokine production leading to increased immune infiltration. This prediction was validated in numerous orthogonal datasets, as well as experimentally in vitro and in vivo by cytokine release and immune cell migration. These findings demonstrate diverse drivers of immune cell infiltration across cancer lineages and may facilitate the clinical adaption of immunotherapies across diverse malignancies.
Highlights
To realize the full potential of immunotherapy, it is critical to understand the drivers of tumor infiltration by immune cells
We classified patients as cytotoxic T lymphocyte (CTL) high based on presence of both the marker CD8 and the cytolytic enzyme granzyme B, and validated this classification based on expression of a second cytolytic enzyme perforin (Fig. 1b)
Likewise consistent with previous observations, neoantigen load was strongly related with CTL levels as shown by the receiveroperator characteristic curve for predicting CTL high patients based on neoantigen burden (Fig. 2a)
Summary
To realize the full potential of immunotherapy, it is critical to understand the drivers of tumor infiltration by immune cells. To understand immune invasion in these cancers, we developed an integrative multi-omics framework, identifying the DNA damage response protein ATM as a driver of cytokine production leading to increased immune infiltration This prediction was validated in numerous orthogonal datasets, as well as experimentally in vitro and in vivo by cytokine release and immune cell migration. Mutational burden has been shown to correspond to efficacy of checkpoint blockade in melanoma, lung cancer, and colorectal cancer[3,5,6,7] This accumulating evidence has resulted in attempts to utilize microsatellite instability, a biomarker for defects in mismatch repair leading to a hyper-mutator phenotype, as a pan-cancer predictive marker for immunotherapy[8]. Mutli-omics network analysis identified phosphorylation of the DNA double-strand break signal transducer ATM as a strong predictor of CTL infiltration that may act by driving expression of key cytokines These predictions were validated using in vitro and in vivo experimental models. No enrichment for patients with high copy number variation or overall mutational load was observed (Supplementary Fig. 2)
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