Functional impairment of infiltrating T cells in human colorectal cancer

Abstract

T cells play a crucial role in preventing the growth and spread of colorectal cancer (CRC). However, immunotherapies against CRC have only shown limited success, which may be due to lack of understanding about the effect of the local tumor microenvironment (TME) on T cell function. The goal of this study was to determine whether T cells in tumor tissue were functionally impaired compared to T cells in non-tumor bowel (NTB) tissue from the same patients. We showed that T cell populations are affected differently by the TME. In the tumor, T cells produced more IL-17 and less IL-2 per cell than their counterparts from NTB tissue. T cells from tumor tissue also had impaired proliferative ability compared to T cells in NTB tissue. This impairment was not related to the frequency of IL-2 producing T cells or regulatory T cells, but T cells from the TME had a higher co-expression of inhibitory receptors than T cells from NTB. Overall, our data indicate that T cells in tumor tissue are functionally altered by the CRC TME, which is likely due to cell intrinsic factors. The TME is therefore an important consideration in predicting the effect of immune modulatory therapies.

Prognostic roles for IL‐2‐producing and CD69+T cell subsets in colorectal cancer patients

“…Previous work has shown that the T cell infiltrate in NTB and tumor of patients with CRC is associated with cancer recurrence and DFS . In Cohort 1, analyzed by flow cytometry, there was a significantly lower frequency of IFN‐γ‐producing CD4 + T cells, as has been previously found and a significantly higher frequency of CD69 + CD4 + T cells in the tumor of patients with recurrent disease than patients without recurrent disease (Figs. a and b ).…”

Regulatory T‐cell heterogeneity and the cancer immune response

“…There is evidence that CD8 + T‐cell populations can also express FOXP3 and have regulatory function. CD8 + FOXP3 + Tregs have been identified in CRC tissue 49 and were able to suppress CD4 + T‐cell proliferation and IFN‐γ production ex vivo 50 . CD8 + FOXP3 + Tregs have also been identified in ovarian cancer patients and higher infiltrates were associated with higher stage of disease 51 .…”

High-Dimensional Mass Cytometric Analysis Reveals an Increase in Effector Regulatory T Cells as a Distinguishing Feature of Colorectal Tumors

“…The lines between each dot are edges that indicate relationships between cells. The eight largest clusters have been identified by a cluster identification number (1)(2)(3)(4)(5)(6)(7)(8). Only the eight largest were labeled, given the relatively low abundance of the remaining eight clusters.…”

“…Both CD3 + T cell and CD8 + T cell infiltration have been associated with improved patient prognosis in numerous patient cohorts in the development of the Immunoscore (2), a method for staging CRC tumors based on CD3 + and CD8 + T cell infiltration at the invasive margin and the center of the tumor. However, the tumor microenvironment (TME) contains highly diverse populations of T cells that are capable of both promoting and hindering tumor progression (3)(4)(5)(6). For example, 50% of patients with an intermediate Immunoscore had disease recurrence in a New Zealand cohort of 32 American Joint Committee on Cancer stage II patients (7); these data highlight the need to further improve outcome prediction.…”