Multimodal genomic features predict outcome of immune checkpoint blockade in non-small-cell lung cancer

Abstract

Despite progress in immunotherapy, identifying patients that respond has remained a challenge. Through analysis of wholeexome and targeted sequence data from 5,449 tumors, we found a significant correlation between tumor mutation burden (TMB) and tumor purity, suggesting that low tumor purity tumors are likely to have inaccurate TMB estimates. We developed a new method to estimate a corrected TMB (cTMB) that was adjusted for tumor purity and more accurately predicted outcome to immune checkpoint blockade (ICB). To identify improved predictive markers together with cTMB, we performed whole-exome sequencing for 104 lung tumors treated with ICB. Through comprehensive analyses of sequence and structural alterations, we discovered a significant enrichment in activating mutations in receptor tyrosine kinase (RTK) genes in nonresponding tumors in three immunotherapy treated cohorts. An integrated multivariable model incorporating cTMB, RTK mutations, smoking-related mutational signature and human leukocyte antigen status provided an improved predictor of response to immunotherapy that was independently validated.

Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival

“…Tumors with higher TMB have been hypothesized to have more neoantigens that can be recognized by the immune system in response to checkpoint inhibition, yet the data presented here and data previously published [2] support the use of substantially different "absolute" TMB thresholds for immunotherapy response prediction across different diseases. Further, evidence suggests that other genomic factors, such as tumor purity and clonal heterogeneity, may further modulate the relationship between TMB and immunotherapy response [57,67]. This suggests an added layer of as-of-yet undefined complexity not captured in the current bulk metrics, and likely related to disease-specific biology.…”

Development of Prognostic Nomogram Based on Immune Scores in Lung Adenocarcinoma Patients

“…A signi cant contribution of immune cells to LADC has been widely accepted [18],and immune gene was thinked as a biomarker for immune response in immunotherapy [19]. Earlier studies also showed that some immune genes are signi cantly related to the prognosis of LADC [20]. In addition, other studies have found that immune gene expression should be included in the current multi-gene test to improve the prognosis of patients with LADC [21,22].…”

Burden of tumor mutations, neoepitopes, and other variants are dubious predictors of cancer immunotherapy response and overall survival

“…Tumors with higher TMB have been hypothesized to have more neoantigens that can be recognized by the immune system in response to checkpoint inhibition, yet the data presented here and data previously published (2) support the use of substantially different "absolute" TMB thresholds for immunotherapy response prediction across different diseases. Further, evidence suggests that other genomic factors, such as tumor purity and clonal heterogeneity, may further modulate the relationship between TMB and immunotherapy response (62,72) . This suggests an added layer of as-of-yet undefined complexity not captured in the current bulk metrics, and likely related to disease-specific biology.…”