Weekly Digests
‹ Back to June

Chromatin states define tumour-specific T cell dysfunction and reprogramming

June 7, 2017

It is well known that tumor-specific CD8+ T cells (TST) found within solid tumors are often dysfunctional and do not affect tumor progression. TST become dysfunctional early on in the tumorigenesis process and exhibit the same characteristics as tumor-reactive tumor-infiltrating lymphocytes (TILs) in late-stage human solid tumors. Philip et al. hypothesized that the dysfunctional state of TST is due to tumor-specific epigenetic changes.

The researchers analyzed the changes in chromatin state of TST during tumor development in mice bearing a tamoxifen-inducible SV40 T antigen (TAG)-expressing liver cancer that progresses from pre-malignant lesions to hepatocellular carcinoma within 60-90 days. Congenically marked naive T cells with specificity for TAG (TCRTAG cells) were adoptively transferred into the mice one day prior to tamoxifen administration. The authors then analyzed the genome-wide chromatin accessibility of liver-infiltrating TCRTAG cells at different time points using ATAC-seq (Assay for Transposase-Accessible Chromatin with high-throughput sequencing) and RNA-seq, and compared it to the epigenetic changes during T cell differentiation in an acute infection model. They found that the TCRTAG cells that encountered the TAG tumor antigen in the pre-malignant liver lesions were rendered dysfunctional, expressed inhibitory receptors PD-1 and LAG3, did not produce IFN-γ or TNFα, and differentiated through two discrete chromatin states.

Plastic, Reprogrammable State 1

  • TCRTAG cells underwent massive chromatin remodeling by day 5 (consistent with effector T cell differentiation in the acute infection model).
  • In vitro culture with IL-15 could restore the effector function of State 1 TCRTAG cells.
  • State 1 TCRTAG cells expressed low levels of CD38 and CD101 cell surface markers.

Fixed, Non-reprogrammable State 2

  • TCRTAG cells underwent further, more limited, chromatin remodeling between days 7 and 14.
  • In vitro culture with IL-15 could not restore the effector function of State 2 TCRTAG cells.
  • State 2 TCRTAG cells expressed high levels of CD38 and CD101.

Consistent with the loss of effector function, the accessibility of transcription factor binding sites in genes encoding inhibitory receptors and negative regulators was increased during progression from the plastic to the fixed dysfunctional state in TCRTAG cells, while the accessibility of co-stimulatory molecule genes was decreased. Very few further chromatin accessibility changes occurred after day 14, even after the cancer progressed to established tumor. Remarkably, the authors found that even memory TCRTAG cells that were adoptively transferred into mice bearing established hepatocellular carcinoma lost their effector function as they progressed through the two dysfunctional states after antigen exposure.

The team focused on two transcription factors they had identified with the global changes in binding site accessibility: NFAT, for which binding site accessibility was increased, and TCF, for which binding sites were closed during T cell dysfunction. Pharmacological modulation of these two transcription factors in mice delayed T cell dysfunction and improved the reprogrammability of TST.

The researchers found that the chromatin accessibility state of patient-derived TILs with high PD-1 expression was most similar to that of the State 2 dysfunctional mouse TST. Human PD-1hi TILs displayed heterogeneous expression of CD38 and CD101 markers, which could potentially be used to identify T cells that are amenable to therapeutic reprogramming, turning dysfunctional TST into an effective antitumor therapy.

by Anna Scherer


M. Philip, L. Fairchild, L. Sun, E.L. Horste, S. Camara, M. Shakiba, A.C. Scott, A. Viale, P. Lauer, T. Merghoub, M.D. Hellmann, J.D. Wolchok, C.S. Leslie & A. Schietinger. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature. 2017 May 25.

In the Spotlight...

Overcoming the Immunosuppressive Tumor Microenvironment of Hodgkin Lymphoma Using Chimeric Antigen Receptor T Cells.

CAR T cells targeting CD123, expressed on tumor cells from most HL patients and on M2-polarized tumor-associated macrophages (TAMs), completely eradicated HL, and led to a durable remission and memory response in 100% of mice in a xenograft model of progressive HL. In vitro, CART123 cells recognized and killed HL tumor cells and immunosuppressive TAMs.

Acquired IFNgamma resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions.

Tumor subclones harbouring inactivating mutations in the IFNγ signaling pathway can be detected in pretreatment biopsies of some melanoma patients or can emerge during immunotherapy treatment, and in some cases IFNγ-resistant melanoma progresses further through silencing of HLA class I antigen presentation, leading to complete CD8+ T-cell resistance.

Antibody-mediated neutralization of soluble MIC significantly enhances CTLA4 blockade therapy.

Combination therapy targeting soluble MIC and CTLA-4 in a transgenic adenocarcinoma mouse model improved the antitumor effect of anti-CTLA-4 therapy by increasing the functional potential of dendritic cells and antigen-specific CD8+ T cells, while also alleviating anti-CTLA-4-induced colitis.

Everything New this Week In...

Close Modal

Small change for you. Big change for us!

This Thanksgiving season, show your support for cancer research by donating your change.

In less than a minute, link your credit card with our partner RoundUp App.

Every purchase you make with that card will be rounded up and the change will be donated to ACIR.

All transactions are securely made through Stripe.