Homogeneity in immune features between colorectal liver metastases better identifies patients with good prognosis compared to pathological response to preoperative chemotherapy

ABSTRACT

In colorectal cancer liver metastases (CRLM), the density of tumor-infiltrating lymphocytes, the expression of class I major histocompatibility complex (MHC-I), and the pathological response to preoperative chemotherapy have been associated with oncological outcomes after complete resection. However, the prognostic significance of the heterogeneity of these features in patients with multiple CRLMs remains under investigation. We used a tissue microarray of 220 mismatch repair-gene proficient CRLMs resected in 97 patients followed prospectively to quantify CD3⁺ T cells and MHC-I by immunohistochemistry. Histopathological response to preoperative chemotherapy was assessed using standard scoring systems. We tested associations between clinical, immunological, and pathological features with oncologic outcomes. Overall, 29 patients (30.2%) had CRLMs homogeneous for CD3+ T cell infiltration and MHC-I. Patients with immune homogeneous compared to heterogeneous CRLMs had longer median time to recurrence (TTR) (30 vs. 12 months, p = .0018) and disease-specific survival (DSS) (not reached vs. 48 months, p = .0009). At 6 years, 80% of the patients with immune homogeneous CRLMs were still alive. Homogeneity of response to preoperative chemotherapy was seen in 60 (61.9%) and 69 (80.2%) patients according to different grading systems and was not associated with TTR or DSS. CD3 and MHC-I heterogeneity was independent of response to pre-operative chemotherapy and of other clinicopathological variables for their association with oncological outcomes. In patients with multiple CRLMs resected with curative intent, similar adaptive immune features seen across metastases could be more informative than pathological response to pre-operative chemotherapy in predicting oncological outcomes.

KEYWORDS:

• Colorectal liver metastasis
• immune score
• prognostic biomarker
• tumor heterogeneity
• tumor infiltrating lymphocytes

Acknowledgments

We thank the patients for providing access to their tissues and data for research; L. Rousseau, J. Bilodeau, and S. Langevin from the CHUM hepatopancreatobiliary cancer biobank for patient recruitment, prospective data, and biospecimen acquisition; L. Meunier and V. Barrès from the CRCHUM histology platform for building the tissue microarray and high-resolution scanning; and A. Cleret-Bohot from the CRCHUM microscopy platform for assistance with automated quantification.

Disclosure statement

Outside the submitted work, S.T. has received consultant fees from Bristol Myers Squibb and Turnstone Biologics, speaking fees from Celgene and Astra Zeneca, and has research funding from Iovance Biotherapeutics and Turnstone Biologics.

Authors’ contributions

D.H. conceptualization, data acquisition and curation, formal analysis, writing – original draft, writing – review and editing; D.S. tumor bloc selection and pathological scoring; P.-A. St-H optimization of automated quantification and preliminary data analysis; N.M. writing-review and editing; F. V.-M., E. B.-S., Z.X.R., M.P., A. R., M. D. M.P., R. Let., R. Lap. patient recruitment, writing-review and editing; A.-M. M.-M. funding acquisition, writing – review and editing; B.N. and G.S. supervision of pathological scoring; S.T. conceptualization, funding acquisition, methodology, data curation, supervision, formal analysis, writing – original draft, writing – review and editing.

Availability of data and material

All raw tissue microarray images and associated marker quantification and patient clinicopathological characteristics are available upon request from the study authors.

Consent for publication

All patients consenting to participate in the above-mentioned biobank and registry consent to publication of anonymized results derived from related IRB-approved scientific projects.

Ethics approval and patient consent

This study was approved by the Centre hospitalier de l’Université de Montréal (CHUM) institutional review board (No. 14.198) and was performed in accordance with the Declaration of Helsinki. All patients provided informed written consent to participate in the CHUM hepatopancreatobiliary cancer biobank and prospective registry associated with this study (No. 09.237).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2253642

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This study was supported by the Université de Montréal Roger Des Groseillers Research Chair in Hepatopancreatobiliary Surgical Oncology. ST and AMMM are Researchers of the Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM)/which receive support from the Fonds de recherche du Québec - Santé (FRQS). ST was supported by the Fonds de recherche du Québec – Santé (FRQ-S) Young Clinician Scientist Seed Grant No. 32633; FRQS Clinician Scientist Junior-1 Salary Award No. 30861; and Institut du Cancer de Montréal establishment award. DH was supported by the FRQ-S phase 1 award for medical residents engaged in clinician-scientist training; NM was supported by the International Hepato-Pancreato-Biliary Association (IHPBA) Kenneth Warren Research Fellowship and Ethicon Inc. (Johnson & Johnson).