Neoadjuvant chemotherapy is associated with a transient increase of intratumoral T-cell density in microsatellite stable colorectal liver metastases

ABSTRACT

Patients with colorectal liver metastases (CLM) commonly receive neoadjuvant chemotherapy (NACT) prior to surgical resection. NACT may induce immunogenic cell death with subsequent recruitment of T-cells to the tumor microenvironment, which could be exploited by immune checkpoint inhibition (ICI). In theory, this could expand the use of ICI to obtain responses also in microsatellite stable colorectal cancer, but evidence to suggest optimal treatment schedules are lacking. In this study, densities of total-, cytotoxic-, helper- and regulatory T-cells were quantified by immunohistochemistry in resected CLM from 92 patients included in the OSLO-COMET trial (NCT01516710). All but one patient had microsatellite stable tumors (91/92). Associations between T-cell densities and clinicopathological parameters were analyzed. Fluoropyrimidine-based NACT (in most cases with addition of oxaliplatin or irinotecan) was administered to 45 patients completed median 8 weeks prior to surgical resection. No overall association was found between NACT administration and intratumoral T-cell densities. However, within the NACT group, a short time interval (<9.5 weeks) between NACT completion and CLM resection was strongly associated with high intratumoral T-cell densities compared to the long-interval and no NACT groups (medians 491, 236, and 292 cells/mm², respectively; P < .0001). The results from this study suggest that the observed increase in intratumoral T-cells after NACT administration may be transient. The significance of this finding should be further explored to ensure that optimal treatment schedules are chosen for studies combining cytotoxic chemotherapy and ICI.

KEYWORDS:

• Liver metastases
• colorectal cancer
• neoadjuvant chemotherapy
• immunogenic cell death
• t-cell densities
• immune check-point inhibition

Acknowledgments

We would like to acknowledge the contributions from the OSLO-COMET study group, Ellen Hellesylt, Department of Pathology, Oslo University Hospital, Oslo, Norway, and Christine Penz and Lars Gustav Lyckander, Department of Pathology, Akershus University Hospital, Lørenskog, Norway.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Supplementary material

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Additional information

Funding

VJD was supported by the Norwegian Research Council; grant # 218325 (to the project: Actionable Targets in Cancer Metastasis – From Bed to Bench to Byte to Bedside project) and the Radium Hospital Foundation.SEM was supported by Norwegian Cancer Society; grant # 182496 (to the project: Colorectal Cancer METastasis - Shaping Anti-tumor IMMunity by Oxaliplatin)The OSLO-COMET trial was funded by the South-Eastern Norway Regional Health Authority grant # 602699.Additional support for analyses was provided by Ivar, Ragna og Morten Hole’s Foundation for cancer research.