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Proteostatic Stress Response is a Mechanistic Driver of T Cell Exhaustion and a New Therapeutic Opportunity for Cancer Immunotherapy

ABSTRACT: Chronic infections and cancer cause T cell dysfunction known as exhaustion due to persistent antigen exposure, suboptimal co-stimulation and a plethora of hostile factors, which dampens protective immunity and limits the efficacy of immunotherapies1-4. The mechanisms behind T cell exhaustion remain poorly understood. Herein, we dissected the proteome of CD8+ exhausted T cells (Tex) across multiple states of exhaustion in the context of both chronic viral infections and cancer. We found that there was a non-stochastic pathway-specific discordance between mRNA and protein dynamics in T effector (Teff) versus Tex cells. We identified a unique proteostatic stress response (PSR) in Tex cells which we termed TexPSR. Contrary to canonical stress responses with reduced protein synthesis5,6, the TexPSR involves increased global translation activity and an upregulation of specialized chaperones, characterized further by the accumulation of protein aggregates, stress granules and autophagy-dominant protein catabolism. We established that disruption of proteostasis alone can convert Teff to Tex cells, and linked TexPSR mechanistically to persistent Akt signaling. Finally, we found that disruption of TexPSR-associated chaperones in CD8+ T cells improved cancer immunotherapy preclinically and demonstrated that high TexPSR feature in T cells in cancer patients confers poor response to immunotherapy clinically. Our findings collectively highlight TexPSR as a hallmark and a mechanistic driver of T cell exhaustion, raising the possibility of targeting proteostasis as a potential novel approach for cancer immunotherapy.

INSTRUMENT(S): Orbitrap Fusion, Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606) Mus Musculus (ncbitaxon:10090)

SUBMITTER: Zihai Li Brian C Searle

PROVIDER: MSV000098609 | MassIVE | Tue Jul 22 19:06:00 BST 2025

SECONDARY ACCESSION(S): PXD066433

REPOSITORIES: MassIVE

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Project description:Immunotherapy has opened hitherto unknown possibilities to treat cancer. Whereas some cancer types (e.g. melanoma) can be efficiently treated, others lack measurable positive effects (e.g. PDAC). Moreover, stratification of responders/non-responders is only possible in some cancer types (e.g. melanoma). Hepatocellular carcinoma (HCC) has a dismal prognosis, limited treatment options and survival benefit, and represents a potential cancer entity for successful immunotherapy. Here, we investigated NASH-triggered HCC in the context PD-1-targeted immunotherapy. Using flow cytometry, single cell RNA sequencing, immunohistochemistry and mass spectrometric analyses, we found a progressive increase of CD8+PD-1+ effector T-cells with a unique profile of exhaustion and activation markers rising with murine and human NASH severity. Notably, late-stage HCC treatment with PD-1-targeted immunotherapy enhanced hepatic carcinogenesis in mice. Dissecting potential mechanisms of action during tumor-initiation and -progression we analyzed the effects of PD-1-targeted immunotherapy at HCC initiation. PD-1-targeted immunotherapy induced a pro-tumorigenic environment, enhanced necro-inflammation and increased NAFLD-activation score (NAS), leading to increased liver cancer incidence, tumor number and nodule size. In contrast, anti-CD8 or anti-CD8/anti-NK1.1 treatment reduced NAS and abrogated the development of liver cancer, thus identifying CD8+PD-1+ T-cells as drivers of liver cancer in NASH-triggered HCC. Increased apoptotic signaling, STAT3 phosphorylation and hepatic proliferation were detected in intra-tumoral liver tissue upon PD-1-targeted immunotherapy. In line, PD-1-/- mice challenged with a NASH diet displayed early onset of hepatocarcinogenesis, corroborating the pro-tumorigenic role of absent or reduced PD-1. Mechanistically PD-1-targeted immunotherapy mainly affected hepatic abundance of CD8+PD-1+ T-cells, instead of altering the quality of Tox+CXCR6+ expressing CD8+PD-1+TNF+CD39+Gzmb+ T-cells found in NASH livers, leading to an aggressive, pro-tumorigenic liver environment. Single-cell mapping of human NASH-, borderline NASH- or unaffected livers corroborated our preclinical NASH results. Moreover, in human NASH livers a correlation of hepatic CD8+, PD-1+, TNF+ T-cells with fibrosis and NASH severity was observed. Accordingly, HCC patients with NASH etiology display a sharp increase in intra- and peri-tumoral CD8+ PD-1+ T-cells. In a cohort of 65 patients recruited across 6 centers in Germany and Austria, patients with NAFLD/NASH-driven HCC responded worse to PD-1-targeted immunotherapy by Nivolumab or Pembrolizumab compared to non-NAFLD patients. This resulted in significant reduced overall survival, in trends of faster disease progression and reduced progression free survival. Histological analysis of livers derived from HCC patients treated with PD-1-targeted immunotherapy displayed high levels of intra and peri-tumoral CD8+ PD-1+ T-cells and Ki67+ hepatocytes. Taken together, these data indicate that PD-1-targeted immunotherapy induces immune-related adverse effects in NAFLD/NASH-driven HCC through CD8+PD-1+ T-cells. Our data call for stratification of HCC patients subjected to PD-1-targeted immunotherapy, with NAFLD being a negative predictor.

Project description:CD8+ T cells are essential components of the body’s immune reaction against viral infections and tumors, capable of eliminating infected and cancerous cells. However, when the antigen cannot be cleared, T cells enter a state known as exhaustion. Exhausted CD8+ T cells are characterized by expression of multiple inhibitory receptors, like PD-1 and TIM3 and reduced capacity to secrete cytokines, and are commonly found in chronic viral infections, like HIV and HBV, as well as in immunosuppressive tumor microenvironments (TME). Cancer and chronic infection also place considerable stress on tissue architecture and function, and while it is clear that chronic antigen contributes to CD8+ T cell exhaustion, less is known about how stress responses in tissues regulate T cell function. Here we show a previously undescribed link between the stress-associated catecholamines adrenaline and noradrenaline and the development of T cell exhaustion through the β1-adrenergic receptor, ADRB1. We identify that exhausted CD8+ T cells express higher levels of ADRB1, and exposure of ADRB1-expressing T cells to catecholamines suppresses cytokine production and impairs T cell proliferation. Genetic or pharmacological ablation of β-adrenergic signaling via ADRB1 reduces development of T cell exhaustion in a chronic infection model and improves cytotoxic functions in tumor-infiltrating lymphocytes (TILs) when combined with immune checkpoint blockade (ICB) therapy in a melanoma model. Extending these findings to an ICB-resistant tumor model of murine pancreatic cancer, we show that beta-blockers and ICB synergize to enhance and reprogram T cell responses. Given that malignant disease is associated with increased systemic catecholamine levels in patients and therapeutic stress reduction improves survival in cancer patients, our results demonstrate a potential link between systemic stress, tumor innervation and immune responses. Our findings show that β-adrenergic signaling constitutes a novel targetable immune checkpoint in CD8+ T cells to rejuvenate antitumor functions. More broadly, our results support further clinical investigation into the application of beta-blockers, which are clinically safe and widely prescribed, as an immunomodulating agent for cancer immunotherapy.

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Proteostatic Stress Response is a Mechanistic Driver of T Cell Exhaustion and a New Therapeutic Opportunity for Cancer Immunotherapy

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