The loss of neoantigens is an important reason for immune escape in multiple myeloma patients with high intratumor heterogeneity

Abstract

ObjectivesIntratumor heterogeneity (ITH) is an important factor for clinical outcomes in patients with multiple myeloma (MM). High ITH has been proven to be a key reason for tumor immune escape and treatment resistance. Neoantigens are thought to be associated with ITH, but the specific correlation and functional basis for this remains unclear.MethodsWe study this question through the whole‐exome sequencing (WES) data from 43 high ITH newly diagnosed MM patients in our center. Mutant allele tumor heterogeneity (MATH) was conducted to quantify ITH. The cutoff value for high intratumor heterogeneity was determined by comparing MATH of different kinds of tumors. NeoPredPipe was performed to predict neoantigens and binding affinity.ResultsCompared to other tumors, MM has a relatively low tumor mutation burden but a high ITH. Patients with high MATH had significantly shorter progression‐free survival times than those with low MATH (p = 0.001). In high ITH samples, there is a decrease in strong‐binding neoantigens (p = 0.019). The loss of strong‐binding neoantigens is a key factor for insensitivity to therapy (p = 0.015). Loss of heterozygosity in HLA was not observed. In addition, patients with fewer neoantigens loss had higher rates of disease remission (p = 0.047). CD8 + T cells (p = 0.012) and NK cells (p = 0.011) decreased significantly in patients with high neoantigens loss rate. A prediction model based on neoantigens was built to evaluate the strength of immune escape.ConclusionThe loss of strong‐binding neoantigens explains why tumors with high ITH have a higher degree of immune escape and may be feasible for deciding the clinical treatment of MM.

CAR T therapies in multiple myeloma: unleashing the future

“…High ITH is associated with tumor immune escape and resistance to treatment. While the connection between neoantigens and ITH is recognized, the specific details and functional implications of this relationship require further elucidation [ 110 ].…”

Targeting Neoantigens in Pancreatic Ductal Adenocarcinoma

“…The number of SNV-predicted neoantigens has been shown to have low (around 3%) immunogenicity [ 60 ]. In the tumors with high intratumor heterogeneity, the immune escape may be due to the loss of strong-binding neoantigens produced by SNVs [ 61 ]. Insertion/deletions (INDELS) can also create neopeptides, but are more frequently responsible for shifts in the reading frame and are self-selected.…”