Milken Institute School of Public Health Poster Presentations (Marvin Center & Video)

Title

Role of Blimp-1 in CD4 T cell exhaustion in cancer

Poster Number

58

Document Type

Poster

Status

Graduate Student - Masters

Abstract Category

Epidemiology and Biostatistics

Keywords

cancer, blimp-1, pd1, CD4, CD8

Publication Date

Spring 2018

Abstract

Abstract

Cancer is the second leading cause of death (8.8 million) globally according to the data published by World Health Organization (WHO) in 2015. Although treatments including surgery, radiotherapy and chemotherapy have been used clinically, these methods still have huge limitations in either curing the disease or prolonging patients’ life with good quality. Recently, highly promising therapies targeting immune checkpoint inhibitors such as programmed cell death protein 1 (PD1) pathway blockade have been brought forward. Nevertheless, with an increasing number of resistance from these therapies that have been observed, treatments do not work as effective as they should be in theory. Thus, it is important to have a closer look on the exact inhibitory mechanisms in tumor microenvironment. CD4 and CD8 T lymphocyte cells play critical roles in human cell-mediated immune response to cancer. However, due to over expression of inhibitory receptors, T cells ultimately lose their functionality which is manifested by decrease in their cytokine producing ability and other effector mechanisms. This stage is referred to as “state of T cell exhaustion”, and it results in the decreased host ability to prevent tumor growth, which leads to the failure of cancer elimination. In a melanoma cancer model, in depth analysis by 12-color flow cytometry showed increased expression of inhibitory markers PD1, 2B4, Tim3, and LAG3 on T cells in tumor bearing mice. However, the levels of inhibitory marker expression were different between CD8 and CD4 T cells. Similarly, cells from lymph nodes (LNs) and tumor-infiltrating lymphocytes (TILs) exhibited different inhibitory receptor expression patterns. By gating on antigen specific CD8 T cells using a surrogate marker strategy, CD44hiCD11ahi CD8 from TILs showed higher expression of all inhibitory markers as compared to the cells from LNs. Furthermore, SPICE analysis revealed that a greater proportion of TILs exhibited concomitant expression of three or more inhibitory markers when compared to CD8 T cells from the LNs. Antigen specific CD4 TILs (CD11ahiCD49dhi) exhibited a prominent increase in PD1 and LAG3 expression compared to LNs, but interestingly, 2B4 and Tim3 expression were similar to antigen specific CD4 T cells from the LNs. The expression of Blimp-1, a transcription factor associated with T cell exhaustion, was elevated in T cells that have the most concomitant increased expressions of several inhibitory markers. This is an agreement with published results from our laboratory which showed that high expression of Blimp-1 by CD4 T cells leads to their dysfunction during chronic toxoplasmosis.

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Role of Blimp-1 in CD4 T cell exhaustion in cancer

Abstract

Cancer is the second leading cause of death (8.8 million) globally according to the data published by World Health Organization (WHO) in 2015. Although treatments including surgery, radiotherapy and chemotherapy have been used clinically, these methods still have huge limitations in either curing the disease or prolonging patients’ life with good quality. Recently, highly promising therapies targeting immune checkpoint inhibitors such as programmed cell death protein 1 (PD1) pathway blockade have been brought forward. Nevertheless, with an increasing number of resistance from these therapies that have been observed, treatments do not work as effective as they should be in theory. Thus, it is important to have a closer look on the exact inhibitory mechanisms in tumor microenvironment. CD4 and CD8 T lymphocyte cells play critical roles in human cell-mediated immune response to cancer. However, due to over expression of inhibitory receptors, T cells ultimately lose their functionality which is manifested by decrease in their cytokine producing ability and other effector mechanisms. This stage is referred to as “state of T cell exhaustion”, and it results in the decreased host ability to prevent tumor growth, which leads to the failure of cancer elimination. In a melanoma cancer model, in depth analysis by 12-color flow cytometry showed increased expression of inhibitory markers PD1, 2B4, Tim3, and LAG3 on T cells in tumor bearing mice. However, the levels of inhibitory marker expression were different between CD8 and CD4 T cells. Similarly, cells from lymph nodes (LNs) and tumor-infiltrating lymphocytes (TILs) exhibited different inhibitory receptor expression patterns. By gating on antigen specific CD8 T cells using a surrogate marker strategy, CD44hiCD11ahi CD8 from TILs showed higher expression of all inhibitory markers as compared to the cells from LNs. Furthermore, SPICE analysis revealed that a greater proportion of TILs exhibited concomitant expression of three or more inhibitory markers when compared to CD8 T cells from the LNs. Antigen specific CD4 TILs (CD11ahiCD49dhi) exhibited a prominent increase in PD1 and LAG3 expression compared to LNs, but interestingly, 2B4 and Tim3 expression were similar to antigen specific CD4 T cells from the LNs. The expression of Blimp-1, a transcription factor associated with T cell exhaustion, was elevated in T cells that have the most concomitant increased expressions of several inhibitory markers. This is an agreement with published results from our laboratory which showed that high expression of Blimp-1 by CD4 T cells leads to their dysfunction during chronic toxoplasmosis.