Tumor-Derived IL33 Promotes Tissue-Resident CD8+ T Cells and Is Required for Checkpoint Blockade Tumor Immunotherapy

Radiotherapy (RT) is a conventional method for clinical treatment of local tumors, which can induce tumor-specific immune response and cause the shrinkage of primary tumor and distal metastases via mediating tumor infiltration of CD8+ T cells. Ionizing radiation (IR) induced tumor regression outside the radiation field is termed as abscopal effect. However, due to the mobilization of immunosuppressive signals by IR, the activated CD8+T cells are not sufficient to maintain a long-term positive feedback to make the tumors regress completely. Eventually, the “hot” tumors gradually turn to “cold”. With the advent of emerging immunotherapy, the combination of immune checkpoint blockade (ICB) and local RT has produced welcome changes in stubborn metastases, especially anti-PD-1/PD-L1 and anti-CTLA-4 which have been approved in clinical cancer treatment. However, the detailed mechanism of the abscopal effect induced by combined therapy is still unclear. Therefore, how to formulate a therapeutic schedule to maximize the efficacy should be took into consideration according to specific circumstance. This paper reviewed the recent research progresses in immunomodulatory effects of local radiotherapy on the tumor microenvironment, as well as the unique advantage for abscopal effect when combined with ICB, with a view to exploring the potential application value of radioimmunotherapy in clinic.

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Abstract 2701: Functionally specialized subsets of exhausted CD8+ T cells mediate tumor control and differentially respond to checkpoint blockade

10.1158/1538-7445.am2019-2701 ◽

2019 ◽

Author(s):

Brian C. Miller ◽

Debattama R. Sen ◽

Rose Al Abosy ◽

Kevin Bi ◽

Yamini V. Virkud ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Checkpoint Blockade ◽

Tumor Control

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Targeting Cbx3/HP1γ Induces LEF-1 and IL-21R to Promote Tumor-Infiltrating CD8 T-Cell Persistence

10.21203/rs.3.rs-343458/v1 ◽

2021 ◽

Author(s):

To-Ha Thai ◽

Phuong Le ◽

Ngoc Ha ◽

Ngan Tran ◽

Andrew Newman ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Transcription Initiation ◽

Cd8 T Cell ◽

Checkpoint Blockade ◽

Cell Based Therapy ◽

Functional Exhaustion ◽

Clinical Models ◽

Therapy Target

Abstract Checkpoint blockade can reverse CD8+ T-cell functional exhaustion, and TCF-1 is essential for this process. However, identifying mechanisms that can prevent functional senescence and potentiate CD8+ T-cell persistence in checkpoint blockade non-responsive tumors remains a challenge. We demonstrate that targeting Cbx3/HP1γ causes augmented transcription initiation, chromatin remodeling at Lef1 and Il21r leading to increased transcriptional activity at these loci. Mechanistic studies show LEF-1 and IL-21R are required for Cbx3/HP1γ-deficient CD8+ effector T cells to persist resulting in improved control of ovarian cancer, melanoma and neuroblastoma in pre-clinical models. Cbx3/HP1γ-deficient CD8+ T cells enhanced persistence in the TME facilitates remodeling of the chemokine/receptor landscape that ensures their optimal tumor invasion at the expense of CD4+ Tregs. Thus, CD8+ T cells heightened effector function consequent to Cbx3/HP1γ deficiency may be distinct from functional reactivation by checkpoint blockade, implicating Cbx3/HP1γ as a viable cancer T-cell-based therapy target for resistant, non-responsive solid tumors.

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Cytocidal macrophages in symbiosis with CD4 and CD8 T cells cause acute diabetes following checkpoint blockade of PD-1 in NOD mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2019743117 ◽

2020 ◽

Vol 117 (49) ◽

pp. 31319-31330

Author(s):

Hao Hu ◽

Pavel N. Zakharov ◽

Orion J. Peterson ◽

Emil R. Unanue

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Autoimmune Diabetes ◽

Critical Role ◽

Nod Mice ◽

Checkpoint Blockade ◽

Cellular Interactions ◽

Activated T Cells ◽

Acute Diabetes ◽

Ifn Γ

Autoimmune diabetes is one of the complications resulting from checkpoint blockade immunotherapy in cancer patients, yet the underlying mechanisms for such an adverse effect are not well understood. Leveraging the diabetes-susceptible nonobese diabetic (NOD) mouse model, we phenocopy the diabetes progression induced by programmed death 1 (PD-1)/PD-L1 blockade and identify a cascade of highly interdependent cellular interactions involving diabetogenic CD4 and CD8 T cells and macrophages. We demonstrate that exhausted CD8 T cells are the major cells that respond to PD-1 blockade producing high levels of IFN-γ. Most importantly, the activated T cells lead to the recruitment of monocyte-derived macrophages that become highly activated when responding to IFN-γ. These macrophages acquire cytocidal activity against β-cells via nitric oxide and induce autoimmune diabetes. Collectively, the data in this study reveal a critical role of macrophages in the PD-1 blockade-induced diabetogenesis, providing new insights for the understanding of checkpoint blockade immunotherapy in cancer and infectious diseases.

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IMMU-52. EFFECTS OF IMMUNE CHECKPOINT BLOCKADE ON ANTIGEN-SPECIFIC CD8+ T CELLS FOR USE IN ADOPTIVE CELLULAR THERAPY

Neuro-Oncology ◽

10.1093/neuonc/noab196.411 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi104-vi104

Author(s):

Elizabeth Ogando-Rivas ◽

Paul Castillo ◽

Noah Jones ◽

Vrunda Trivedi ◽

Jeffrey Drake ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cellular Therapy ◽

Checkpoint Inhibitors ◽

Cell Subset ◽

Checkpoint Blockade ◽

Immune Checkpoints ◽

Effector Memory ◽

Dependent Manner

Abstract BACKGROUND Adoptive T-cell therapies have been successfully used as treatment for patients diagnosed with advanced cancers. Unfortunately, for some refractory cancers, they have failed. To overcome this, checkpoint inhibitors have shown to rescue immune anti-tumor responses. We hypothesized that in-vitro checkpoint blockade during T-cell stimulation and expansion with RNA-pulsed dendritic cells may enhance the activity of antigen-specific T-cells and improve the efficacy of ACT platforms. METHODS Human PBMCs were isolated from CMV seropositive donors to generate DCs and pulsed them with CMVpp65-mRNA to educate T-cells in co-culture for 15-days. We targeted pp65 antigen which is ubiquitously expressed by glioblastoma cells. Three checkpoint blockade conditions were evaluated (anti-PD1, anti-Tim3 and anti-PD1+Tim3). IL2 was added every 3 days as well as the blockade antibodies. Immunephenotyping was performed on Day-0 and Day-15. Polyfunctional antigen specific responses were evaluated upon rechallenge with CMVpp65 peptides. RESULTS CMVpp65 activated CD8+ T-cells upregulate Lag3 and Tim3 (p= < 0.0001). Tim3 blockade alone or in combination led to a significant upregulation of Lag3 expression on CD8+pp65Tetramer+ central memory, effector memory, and TEMRA T-cells. This latter T-cell subset uniquely maintain double-positive Tim3/Lag3 expression after blockade. In contrast, PD-1 blockade had minimal effects on Tim3 or Lag3 expression. In addition, IFN-g secretion was reduced in T-cells treated with Tim3 blockade in a dose-dependent manner (p= 0.004). CONCLUSION In this study, we have identified a potential activating component of Tim3 and linkage between Tim3 and Lag3 signaling upon blocking Tim3 axis during T-cell antigen presenting cell interactions that should be considered when targeting immune checkpoints for clinical use.

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