Abstract
Background: 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.Methods: 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, in vivo depletion and ex vivo stimulation. Furthermore, the anti-tumor effect of the single drug or combined therapy with anti-PD1 were also assessed.Results: 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 CD38loCD101loTIM-3−TCF-1hi 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.Conclusions: 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.
Highlights
Colorectal cancer (CRC) is the second leading cause of cancer death in the United States today, with approximately 50,000 deaths per year [1]
We obtained similar results in the CT26 colon carcinoma model (Figures 1D,E). Together these indicate that FOLFOX effectively controls tumor growth and prolongs survival in murine CRC models similar to what is seen in human patients
Since FOLFOX therapy is a current first-line therapy in CRC patients [21] and significantly outperformed single agent therapy (Figure S1), we focused on the effect of FOLFOX on antitumor immunity
Summary
Colorectal cancer (CRC) is the second leading cause of cancer death in the United States today, with approximately 50,000 deaths per year [1]. While recent advances in immune based therapy have significantly improved cancer related outcomes in patients with other malignancies, these results have not yet extended to the majority of patients with CRC [2]. This is somewhat surprising given increasing evidence that suggests the immune response is important for survival, recurrence, and therapeutic efficacy in CRC patients [3,4,5]. The effect of FOLFOX on TILs is poorly understood 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. 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
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