Abstract
Blockade of inhibitory immune checkpoints (ICs) is a promising therapeutic approach; however, it has shown limited success in some cancers including colorectal cancer (CRC). The tumor microenvironment (TME) is largely responsible for response to therapy, and its constituents may provide robust biomarkers for successful immunotherapeutic approaches. In this study, we performed phenotypical characterization and critical analyses of key inhibitory ICs and T regulatory cell (Treg)-related markers on CD4+ T cell subsets in CRC patients, and compared with normal colon tissues and peripheral blood from the same patients. We also investigated correlations between the levels of different CD4+ T cell subsets and the clinicopathologic features including disease stage and tumor budding. We found a significant increase in the levels of CD4+FoxP3+Helios+ T cells, which represent potentially highly immunosuppressive Tregs, in the CRC TME. Additionally, tumor-infiltrating CD4+ T cells upregulated programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), T cell immunoglobulin and mucin domain-3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3). We also characterized the expression of PD-1, CTLA-4, TIM-3, and LAG-3 on different CD4+FoxP3−/+Helios−/+ T cell subsets. Interestingly, we found that CTLA-4, TIM-3, and LAG-3 were mainly co-expressed on FoxP3+Helios+ Tregs in the TME. Additionally, FoxP3high Tregs expressed higher levels of Helios, CTLA-4 and TIM-3 than FoxP3low T cells. These results highlight the significance of Tregs in the CRC TME and suggest that Tregs may hamper response to IC blockade in CRC patients, but effects of different IC inhibition regimes on Treg levels or activity warrants further investigations. We also found that CD4+CTLA-4+ T cells in circulation are increased in patients with advanced disease stage. This study simultaneously provides important insights into the differential levels of CD4+ T cell subpopulations and IC expression in CRC TME, compared to periphery and associations with clinicopathologic features, which could be used as potential biomarkers for CRC progression and response to therapy.
Highlights
The tumor immune microenvironment (TIME) is largely accountable for response to immunotherapeutic modalities, and better analyses of its constituents can help develop robust biomarkers to identify patients who would respond to immunotherapy [1]
We investigated the levels of CD4+ T cells in circulation, normal colon tissues and in the tumor microenvironment (TME) of colorectal cancer (CRC) patients
In agreement with previous reports, we found that CD4+ T cells accumulate in colorectal tumors, compared with normal tissues but were lower compared to their levels in circulation (PBMC; 31.4 ± 2.0 vs. NILs; 11.5 ± 1.0 vs. TILs; 22.0 ± 2.1, Figure 1A)
Summary
The tumor immune microenvironment (TIME) is largely accountable for response to immunotherapeutic modalities, and better analyses of its constituents can help develop robust biomarkers to identify patients who would respond to immunotherapy [1]. DNA fragments or tumor cells budded off from the primary tumor sites may be detected in “liquid biopsies” and used as potential biomarkers for initiation of effective anti-tumor therapies [2, 3]. Current treatments for primary and metastatic CRC primarily include laparoscopic surgeries, radiotherapy, and neoadjuvant and palliative chemotherapies [6, 7]. Pembrolizumab, an immune checkpoint (IC) inhibitor [anti-programmed cell death protein 1 (PD-1)], was recently granted Food and Drug Authority (FDA) approval for treating unresectable or metastatic solid tumors, including CRC, with microsatellite instability high (MSI-H) or DNA mismatch repair deficiency (dMMR) [8, 9]
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