T cell factor 1 (TCF-1) defines T cell differentiation in colorectal cancer

Kelly Tran; Anita N Kumari; Dinesh Raghu; Daniel R A Cox; Su Kah Goh; Marcos V Perini; Vijayaragavan Muralidharan; Niall C Tebbutt; Andreas Behren; John Mariadason; David S Williams; Lisa A Mielke

doi:10.1016/j.isci.2024.110754

T cell factor 1 (TCF-1) defines T cell differentiation in colorectal cancer

iScience. 2024 Aug 22;27(9):110754. doi: 10.1016/j.isci.2024.110754. eCollection 2024 Sep 20.

Authors

Kelly Tran^{1

2

3}, Anita N Kumari^{1

2}, Dinesh Raghu^{1

2}, Daniel R A Cox^{4

5}, Su Kah Goh^{4

5}, Marcos V Perini^{4

5}, Vijayaragavan Muralidharan^{4

5}, Niall C Tebbutt^{1

2

4

6}, Andreas Behren^{1

2}, John Mariadason^{1

2}, David S Williams^{1

2

7}, Lisa A Mielke^{1

2

3}

Affiliations

¹ Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.
² School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia.
³ La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC, Australia.
⁴ Department of Surgery (Austin Precinct), University of Melbourne, Melbourne, VIC, Australia.
⁵ HPB & Liver Transplant Surgery Unit, Department of Surgery, Austin Health, Heidelberg, VIC, Australia.
⁶ Department of Medical Oncology, Austin Health, Heidelberg, VIC, Australia.
⁷ Department of Pathology, Austin Health, Heidelberg, VIC, Australia.

Abstract

The presence of precursor to exhausted (T_pex) CD8⁺ T cells is important to maintain robust immunity following treatment with immune checkpoint inhibition (ICI). Impressive responses to ICI are emerging in patients with stage II-III mismatch repair (MMR)-deficient (dMMR) colorectal cancer (CRC). We found 64% of dMMR and 15% of mismatch repair-proficient (pMMR) stage III CRCs had a high frequency of tumor infiltrating lymphocytes (TIL-hi). Furthermore, expression of TCF-1 (Tcf7) by CD8⁺ T cells predicted improved patient prognosis and T_pex cells (CD3⁺CD8⁺TCF-1⁺PD-1⁺) were abundant within lymphoid aggregates of stage III CRCs. In contrast, CD3⁺CD8⁺TCF-1^-PD-1⁺ cells were more abundant at the invasive front and tumor core, while γδ T cells were equally abundant in all tumor areas. Interestingly, no differences in the frequency of T_pex cells were observed between TIL-hi dMMR and TIL-hi pMMR CRCs. Therefore, T_pex cell function and ICI response rates in TIL-hi CRC warrants further investigation.

Keywords: Cancer; Components of the immune system; Immunology.