Higher Levels of Tumour-Infiltrating Lymphocytes (TILs) are Associated with a Better Prognosis, While CDK5 Plays a Different Role Between Nonmetastatic and Metastatic Colonic Carcinoma

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Abstract

Objective

We investigated the prognostic value of cyclin-dependent kinase 5 (CDK5) in a true population-based cohort of patients with colon cancer.

Methods

1. Immunohistochemical (IHC) staining was used to retrospectively analyse the expression of CDK5 in colon cancer tissue samples of 296 patients. The χ2 test, Kaplan-Meier method and Cox proportional regression model were used to analyse the difference between the patients with differential expression of CDK5 and with different stages (metastatic and nonmetastatic); 2. The number of tumour-infiltrating lymphocytes (TILs) in tumour sections was determined, and its relationship with prognosis was explored.

Results

1. Among 296 patients stained for CDK5, 18 cases (6.09%) showed negative expression, 77 cases (26.01%) showed weak expression (+1), 124 cases (41.89%) showed medium positive expression (2+), and 77 cases (26.01%) showed strong positive expression (3+). The expression of CDK5 was neither related to mismatch repair nor TILs ( p > .05). In non-metastatic patients, longer progression-free survival (PFS) and cancer-specific survival (CSS) were observed in patients with high CDK5 expression (2+ or 3+) than low CDK5 expression (- or 1+), while in metastatic disease, the opposite was true ( p < .001). 2. TILs in 226 patients were detected in the study. Among them, 115 cases (50.88%) showed a low number of TILs (TILs-L), and 111 cases (49.12%) showed a high number of TILs (TILs-H). Patients with a TIL ratio greater than .2 had a significantly better CSS ( p < .001) or PFS ( p = .008 ) than patients with a lower TIL ratio. By multivariate analysis, TILs-H was a protective factor for CSS, however failed to reach a significant difference (hazard ratio: .59, 95% CI: .33∼1.06, p = .079 ), and so was the PFS (HR: .65, 95% CI: .29∼1.43, p = .279 ).

Conclusion

High expression of CDK5 indicates a good prognosis in nonmetastatic colon cancer, while it is the opposite in metastatic colon cancer, and the expression of CDK5 is unrelated to TILs. Patients with TIL-H have a better prognosis, with a proper cut-off value of 20% for colon cancer.

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Most cited references 32

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The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.

Erik von Elm, Douglas G. Altman, Matthias Egger … (2008)

Much biomedical research is observational. The reporting of such research is often inadequate, which hampers the assessment of its strengths and weaknesses and of a study's generalizability. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative developed recommendations on what should be included in an accurate and complete report of an observational study. We defined the scope of the recommendations to cover 3 main study designs: cohort, case-control, and cross-sectional studies. We convened a 2-day workshop in September 2004, with methodologists, researchers, and journal editors, to draft a checklist of items. This list was subsequently revised during several meetings of the coordinating group and in e-mail discussions with the larger group of STROBE contributors, taking into account empirical evidence and methodological considerations. The workshop and the subsequent iterative process of consultation and revision resulted in a checklist of 22 items (the STROBE Statement) that relate to the title, abstract, introduction, methods, results, and discussion sections of articles. Eighteen items are common to all 3 study designs and 4 are specific for cohort, case-control, or cross-sectional studies. A detailed Explanation and Elaboration document is published separately and is freely available at http://www.annals.org and on the Web sites of PLoS Medicine and Epidemiology. We hope that the STROBE Statement will contribute to improving the quality of reporting of observational studies.

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Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Dung Le, Jennifer N. Durham, Kellie N Smith … (2017)

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.

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Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients.

Roy S. Herbst, Jean-Charles Soria, Marcin Kowanetz … (2014)

The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the 'cancer immunity cycle' by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing. The PD-L1-PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.

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Author and article information

Journal

Journal ID (nlm-ta): Cancer Control

Journal ID (iso-abbrev): Cancer Control

Journal ID (hwp): spccx

Journal ID (publisher-id): CCX

Title: Cancer Control : Journal of the Moffitt Cancer Center

Publisher: SAGE Publications (Sage CA: Los Angeles, CA )

ISSN (Print): 1073-2748

ISSN (Electronic): 1526-2359

Publication date (Electronic): 11 April 2023

Publication date Collection: Jan-Dec 2023

Volume: 30

Electronic Location Identifier: 10732748231169396

Affiliations

[1 ]Department of Medical Oncology, The Affiliated Jinhua Hospital, Ringgold 117946, universityZhejiang University School of Medicine; , Jinhua, China

[2 ]Department of Pathology, The Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China

[3 ]Department of Medical Imaging, The Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China

Author notes

[*]Jianfei Fu, Department of Medical Oncology, the Affiliated Jinhua Hospital, Zhejiang University School of Medicine, 365 Renmin East Road, Wucheng District, Jinhua City 321000, China. Email: 11218276@ 123456zju.edu.cn

[*]

Contributed to this work equally

Author information

Jianfei Fu https://orcid.org/0000-0002-3036-1056

Article

Publisher ID: 10.1177_10732748231169396

DOI: 10.1177/10732748231169396

PMC ID: 10113770

PubMed ID: 37039746

SO-VID: 3dc31e31-3aca-4ffb-ad44-81b3e3cde48a

License:

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

History

Funding

Funded by: Natural Science Foundation of Zhejiang Province, FundRef https://doi.org/10.13039/501100004731;

Award ID: LY19H160020

Funded by: Jinhua Science and Technology Bureau, FundRef https://doi.org/10.13039/501100008092;

Award ID: 2019-3-013

Award ID: 2021-3-080

Award ID: 2022-3-099

Award ID: 2022-4-089

Funded by: the General Program of Scientific Research of Jinhua Central Hospital;

Award ID: JY2021-2-10

Funded by: the Key Program of Scientific Research of Jinhua Central Hospital;

Award ID: JY2021-1-01

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cover-date January-December 2023

Keywords: cyclin-dependent kinase 5,tumour-infiltrating lymphocytes,colon carcinoma,prognosis

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Keywords: cyclin-dependent kinase 5, tumour-infiltrating lymphocytes, colon carcinoma, prognosis

Higher Levels of Tumour-Infiltrating Lymphocytes (TILs) are Associated with a Better Prognosis, While CDK5 Plays a Different Role Between Nonmetastatic and Metastatic Colonic Carcinoma

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IODP Expedition 400: NW Greenland Glaciated Margin

Most cited references 32

The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients.

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