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Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function

ABSTRACT: Tumors that contain tumor-infiltrating lymphocytes (TIL) with tissue-resident memory T cells (TRM) features are associated with better patient prognoses. While CD8+ T cells that target tumors often fail to restrain tumor growth due to progressive T cell exhaustion, pathogen-specific TRM survey tissues and sustain protective capacity for years. We identified protein homeostasis (proteostasis)-related E3 ubiquitin ligase genes shared by TRM and progenitor-exhausted TIL (TPEX), that are lost as TIL become terminally-exhausted (TEX). Sustained ligase expression led to increased TCF1+ T cell accumulation and improved anti-tumor function and less T cell exhaustion in chronic infection. Loss-of-function in cancer models impaired TIL accumulation and function and altered T cell differentiation in response to acute infection. Low-input mass spectrometry revealed abundant expression of protein degradation pathways by TEX, yet they accumulated unfolded proteins. Ligase overexpression rescued unfolded protein accumulation in TEX, demonstrating their functional contribution to proteostasis. Ligase overexpression in combination with immune checkpoint blockade led to improved survival from murine melanoma, demonstrating that the relationship between proteostasis and T cell differentiation opens up new avenues for cancer immunotherapy.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): T Cell

SUBMITTER: Xuezhen Ge

LAB HEAD: Eric Bennett

PROVIDER: PXD070932 | Pride | 2026-04-21

REPOSITORIES: Pride

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			Action	DRS
	441_15_TEM_R1_Slot1-15_1_15143.d.zip	Other
	441_16_TEM_R2_Slot1-16_1_15144.d.zip	Other
	441_17_TEM_R3_Slot1-17_1_15145.d.zip	Other
	441_18_TEM_R4_Slot1-18_1_15146.d.zip	Other
	441_19_TRM_R1_Slot1-19_1_15148.d.zip	Other

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Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function

Project description:Tumors that contain tumor-infiltrating lymphocytes (TIL) with tissue-resident memory T cells (TRM) features are associated with better patient prognoses. While CD8+ T cells that target tumors often fail to restrain tumor growth due to progressive T cell exhaustion, pathogen-specific TRM survey tissues and sustain protective capacity for years. We identified protein homeostasis (proteostasis)-related E3 ubiquitin ligase genes shared by TRM and progenitor-exhausted TIL (TPEX), that are lost as TIL become terminally-exhausted (TEX). Sustained ligase expression led to increased TCF1+ T cell accumulation and improved anti-tumor function and less T cell exhaustion in chronic infection. Loss-of-function alleles in T cells challenged with cancer models impaired TIL accumulation and function and altered T cell differentiation in response to acute infection. Mass spectrometry revealed abundant expression of protein degradation pathways by TEX, yet they accumulated unfolded proteins. Ligase overexpression rescued unfolded protein accumulation in TEX, demonstrating their functional contribution to proteostasis. Ligase overexpression in combination with immune checkpoint blockade led to improved survival from murine melanoma, demonstrating that the relationship between proteostasis and T cell differentiation opens up new avenues for cancer immunotherapy.

2026-04-30 | PXD067417 | Pride

Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function

Project description:Tumors that contain tumor-infiltrating lymphocytes (TIL) with tissue-resident memory T cells (TRM) features are associated with better patient prognoses. While CD8+ T cells that target tumors often fail to restrain tumor growth due to progressive T cell exhaustion, pathogen-specific TRM survey tissues and sustain protective capacity for years. We identified protein homeostasis (proteostasis)-related E3 ubiquitin ligase genes shared by TRM and progenitor-exhausted TIL (TPEX), that are lost as TIL become terminally-exhausted (TEX). Sustained ligase expression led to increased TCF1+ T cell accumulation and improved anti-tumor function and less T cell exhaustion in chronic infection. Loss-of-function in cancer models impaired TIL accumulation and function and altered T cell differentiation in response to acute infection. Low-input mass spectrometry revealed abundant expression of protein degradation pathways by TEX, yet they accumulated unfolded proteins. Ligase overexpression rescued unfolded protein accumulation in TEX, demonstrating their functional contribution to proteostasis. Ligase overexpression in combination with immune checkpoint blockade led to improved survival from murine melanoma, demonstrating that the relationship between proteostasis and T cell differentiation opens up new avenues for cancer immunotherapy.

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Project description:CD8+ tumor-infiltrating lymphocytes (TIL) often fail to restrain tumor growth due to differentiation to T cell exhaustion. In healthy tissues, tissue-resident memory T cells (TRM) survey tissues and sustain protective capacity for years, and tumors that contain TIL with TRM-features are associated with better patient prognosis. We identified protein homeostasis (proteostasis) significant in distinguishing TRM and progenitor-exhausted TIL (TPEX) from terminally-exhausted TIL (TEX) by identifying multiple E3 ubiquitin ligases that maintain T cell differentiation potential. Sustained ligase-expression in TIL enhanced T cell accumulation, preserved stem-like TCF1+ populations, and improved anti-tumor function, whereas ligase loss-of-function impaired TIL and altered T cell differentiation in acute infection. TEX experience a loss of proteostasis, marked by unfolded protein accumulation despite functional proteasomes. Enforced ligase expression rescued this unfolded protein accumulation in TIL and improved immunotherapy responses, demonstrating the role of proteostasis in maintaining differentiation potential and identifying new avenues for advancing cancer immunotherapies.

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Project description:Identifying signals that govern the differentiation of tumor-infiltrating CD8 + T cells (CD8 + TILs) towards exhaustion can improve current therapeutic approaches for cancer. Here, we show that type I interferons (IFN-Is) act as environmental cues enhancing terminal CD8 + T cell exhaustion in tumors. We found enrichment of IFNIs-stimulated genes (ISGs) within exhausted CD8 + T cells (Tex cells) in patients across various cancer types, with heightened ISG levels correlating with poor response to immune checkpoint blockade (ICB) therapy. In preclinical models, CD8 + TILs devoid of IFN-Is signaling developed less exhaustion features, provided better tumor control and showed greater response to ICB-mediated rejuvenation. Mechanistically, chronic IFN-Is stimulation perturbed lipid metabolism and redox balance in Tex cells, leading to aberrant lipid accumulation and elevated oxidative stress. Collectively, these defects promoted lipid peroxidation, which potentiated metabolic and functional exhaustion of Tex cells. Thus, cell intrinsic IFN-Is signaling regulates the extent of CD8+ TIL exhaustion, and has important implications for 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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