Tumor-infiltrating lymphocytes (TIL) often fail to restrain tumor growth due to progressive differentiation into an "exhausted" state. Tissue-resident memory T cells (TRM) maintain protection from infection for years in healthy tissues, and patient tumors that contain TIL with TRM features are associated with better prognosis. Proteomic and transcriptomic profiling of T cell populations identified proteostasis as a significant factor distinguishing TRM and progenitor-exhausted TIL from terminally exhausted TIL, including loss of E3 ubiquitin ligases NEURL3, RNF149, and WSB1, with accumulation of unfolded proteins despite functional proteasome activity. Enforced expression of these ligases in T cells preserved stem-like TCF1+ populations and improved function in tumors and chronic infection, whereas deficiency impaired TIL and altered T cell differentiation during acute infection. Sustained ligase expression rescued the accumulation of unfolded proteins in TIL and improved immunotherapy outcomes in preclinical models, underscoring the critical role of proteostasis in TIL function and highlighting a promising avenue for advancing cancer immunotherapy.

Differential expression between normal chr1 and gain(1q) MM patients with t(4;14) translocation

Impact of additional chromosome 1 structural events on outcome A.Effect of amp(1q) with or without a total (TT) gain on PFS B. Effect of amp(1q) on OS

Differential expression between patients with no 1q gain and those with a gain(1q:CKS1B). A. All genes that are differentially expressed

Differential expression between normal chr1 and gain(1q) MM patients with t(11;14) translocation

Methylation probe intensity across chromosome 1. Heatmap representation of the beta value for all probes across chromosome 1, the probes a presented in a genomic coordinate sorted fashion. The recurrent regions of deletion, gain, templated insertion, and chromothripsis have be highlighted along with the cytoband information for reference.

Supplemental Spreadsheet 8: Differential expression between normal chr1 and whole-arm gains group MM patients

Common dependency pathway analysis

List of dysregulated oncogenes, tumor suppressor genes, and fusion proteins in the presence or absence of gain(1q) based on the Cancer Gene Census

Genes with increased dependency in cell lines with del(1p) [part A] Genes with increased dependency in cell lines with del(1p) [part B]

Genes with increased dependency in cell lines with gain(1q).

Bayes Factor output between genetic variables Correlation analysis between deletion region, gain regions, and other genetic events

Recurrent regions of chromothripsis and chromoplexy together with the candidate genes located within the regions. A. CHromothripsis B. Templated Instertion

List of GEP70 genes located on chromosome 1 and their cytoband location. Cytoband

Concurrent Hypomethylation and Overexpression Probes. The dot plot (top) displays the distribution of statistically significant CpG probes with difference in group mean methylation beta value, where the greater the value is a proxy for loss of methylation at the CpG probe. The probes are oriented by genomic locus across chromosome 1 with annotations for the midpoint of the recurrent gained regions on the 1q arm. The area graph (bottom) displays the ratio of probes that are significantly differentially methylated in any given 2MB window across chromosome 1. The highlighted region corresponds to the 1q arm.

Chromatin state of different SV regions. The CT1 region at 1p36.11-1p34.3 is comprised of greater than 74% A-compartment (range 74-100%); CT2 at 1p33-1p32.3 comprises both inactive (range 35-59%) and active chromatin (range 41-65%) and, CT3 at 1p13.3-1p12, overlaps with TI1, had greater variability with 86% A-compartment in U266 while only 1% in KMS11. TI1 region predominantly laid in B-compartment (range 63-73%) and TI2 lay in an almost entirely active compartment (range 91-100%). NBC=Naïve B-cell, MBC=Memory B-cell, GCBC=Germinal Center B-cell, PC=plasma cell.

Recurrent regions of copy number gain and loss together with the candidate genes located within the regions.

Correlation between age, telomere length and 1q gain subtype. A. Correlation between telomere length and chromosome 1 rearrangement subtype B. Correlation between age and chromosome 1 rearrangement subtype