Is tumor mutational burden predictive of response to immunotherapy?

Abstract

Cancer immunotherapy by immune checkpoint blockade (ICB) is effective for several cancer types 1, however, its clinical use is encumbered by a high variability in patient response. Several studies have suggested that Tumor Mutational Burden (TMB) correlates with patient response to ICB treatments 2–6, likely due to immunogenic neoantigens generated by novel mutations accumulated during cancer progression 7. Association of TMB and response to checkpoint inhibitors has become widespread in the oncoimmunology field, within and across cancer types 7–11, and has led to the development of commercial TMB-based biomarker platforms. As a result, patient prioritization for ICB based on individual TMB level was recently approved by the FDA 12. Here we revisit the association of mutational burden with response to checkpoint inhibitors by aggregating pan-cancer data of ICB-treated patients with whole-exome sequencing and clinical annotation. Surprisingly, we find little evidence that TMB is predictive of patient response to immunotherapy. Our analysis suggests that previously reported associations arise from a combination of confounding disease subtypes and incorrect statistical testing. We show that using a TMB threshold for clinical decisions regarding immunotherapy could deprive potentially responding patients of receiving efficacious and life-extending treatment. Finally, we present a simple mathematical model that extends the neoantigen theory, is consistent with the lack of association between TMB and response to ICB and highlights the role of immunodominance. Our analysis calls for caution in the use of TMB as a biomarker and emphasizes the necessity of continuing the search for other genetic and non-genetic determinants of response to immunotherapy.

Mutation and Microsatellite Burden Predict Response to PD-1 Inhibition in Children with Germline DNA Replication Repair Deficiency

“…There is increasing evidence that responses to ICI cannot be predicted by single biomarker. 73,74,19,75 Our data confirm that this is true in RRD cancers which are driven by dysfunction in both SNV and MS-indel repair. Although initially TMB was thought to be the sole contributor to immune response in hypermutant cancers 22 , indels and MS-indels have been suggested to be the main drivers of response to ICI in MMR-deficient cancers 3,49,76 .…”

“…13 However, despite the dramatic anti-tumour effects reported in several hypermutant adult cancers, [14][15][16] these responses are sustained in only a subset of patients. 17,18 The role of TMB in determining the nature and duration of response is not well-established [19][20][21] . Other studies have also raised questions regarding the role of TMB and PD-ligand 1 (PD-L1) expression as robust biomarkers of response to ICI.…”

“…Other studies have also raised questions regarding the role of TMB and PD-ligand 1 (PD-L1) expression as robust biomarkers of response to ICI. 20,[22][23][24] In contrast, MMR-deficient colorectal carcinomas are responsive to ICI due to excess MSI [25][26][27][28] , suggesting that biomarkers like TMB 29 , MSI or PD-L1 expression may not be individually sufficient to drive immune responses following ICI across diverse cancer types 19,21 .…”

Deconvolving clinically relevant cellular immune crosstalk from bulk gene expression using CODEFACS and LIRICS

“…Prior work has led to the prevailing hypothesis that elevated tumor mutation burden in mismatch repair deficient tumors leads to more neoantigens, and thus is more likely to activate a host immune response against tumor cells 16,[19][20][21] . However, not all tumor types with elevated tumor mutation burden have similar response rates to anti-PD1 22,23 , and recent studies have revealed that T cells recognize and respond to only a few neoantigens per tumor [24][25][26][27] . More generally, when looking at non-synonymous tumor mutation burden, MSI and survival data across the TCGA collection (Fig 3A,B, borrowed from 28,29 .…”

Identification of combinations of somatic mutations that predict cancer survival and immunotherapy benefit

“…However, the MSI-H marker is limited to gastrointestinal and endometrial cancers, where mismatch repair deficiency is observed almost exclusively ( 33 ). In addition, the predictive signal of TMB-H status can be confounded by disease subtype ( 34 , 35 ). When considered individually, some cancer types do not show association between TMB-H and survival with anti-PD1 immune checkpoint blockade treatment ( 31 , 34 , 35 ) although such association is strongly evident in non small cell lung cancers ( 30 , 34 ).…”