AUTHOR=Guan Yue , Kraus Sean G. , Quaney Michael J. , Daniels Mark A. , Mitchem Jonathan B. , Teixeiro Emma 

TITLE=FOLFOX Chemotherapy Ameliorates CD8 T Lymphocyte Exhaustion and Enhances Checkpoint Blockade Efficacy in Colorectal Cancer

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.00586

DOI=10.3389/fonc.2020.00586

ISSN=2234-943X

ABSTRACT=<p><bold>Background:</bold> Colorectal cancer (CRC) is the third most common malignancy worldwide. The presence of CD8 tumor-infiltrating T lymphocytes (TILs) is associated with improved prognosis and therapeutic response in CRC patients. FOLFOX chemotherapy is a standard first-line treatment for patients with CRC. Yet, the effect of FOLFOX on TILs is poorly understood. Specifically, it is unclear whether FOLFOX therapy impacts the phenotype and functionality of tumor antigen specific TILs. Immune checkpoint blockade (ICB) has significantly improved clinical outcome of cancer treatment but has shown limited efficacy in CRC patients. Recently, ICB efficiency has been linked to reinvigoration of T cells with a non-terminally dysfunctional phenotype. Here, we investigate the effect of FOLFOX on CD8 T cell tumor accumulation, phenotype and function and tested the combination of FOLFOX and ICB to improve tumor regression.</p><p><bold>Methods:</bold> A mouse model of CRC expressing a human tumor antigen was used to study the effect of FOLFOX on tumor growth and TILs phenotype and function. Tetramers were used to identify and monitor phenotype and function of tumor specific TILs. The phenotype and function of TILs were compared between FOLFOX and control treatment through flow cytometry, <italic>in vivo</italic> depletion and <italic>ex vivo</italic> stimulation. Furthermore, the anti-tumor effect of the single drug or combined therapy with anti-PD1 were also assessed.</p><p><bold>Results:</bold> We show that FOLFOX treatment effectively controlled tumor burden and this was dependent on CD8 T cells. FOLFOX enabled TILs to remain in a functional differentiation state characterized by lower levels of inhibitory receptors PD-1 and TIM-3 and a CD38<sup>lo</sup>CD101<sup>lo</sup>TIM-3<sup>−</sup>TCF-1<sup>hi</sup> phenotype. Consistent with this, TILs from FOLFOX treated tumors exhibited higher effector function. Importantly, while anti-PD-1 treatment alone had no significant effect on tumor burden, FOLFOX and PD-1 checkpoint blockade combination showed significant tumor control.</p><p><bold>Conclusions:</bold> FOLFOX treatment impacts the phenotype and function of TILs making them more responsive to checkpoint blockade. This study highlights the importance of combining chemotherapy and ICB to optimize treatment efficacy in patients with colorectal cancer.</p>