Tumor-Infiltrating Immune Cells Are More Abundant in Lung Metastases From Colorectal Cancer Than in Paired Primary Tumors and Their Prognostic Value Depends on Adjuvant Chemotherapy

Kuznyecov, Danyil; Siesing, Christina; Vidarsdottir, Halla; Eberhard, Jakob; Brunnström, Hans; Leandersson, Karin; Jirström, Karin

Tumor-Infiltrating Immune Cells Are More Abundant in Lung Metastases From Colorectal Cancer Than in Paired Primary Tumors and Their Prognostic Value Depends on Adjuvant Chemotherapy

Mark

Kuznyecov, Danyil ^LU ; Siesing, Christina ^LU ; Vidarsdottir, Halla ^LU ; Eberhard, Jakob ^LU ; Brunnström, Hans ^LU

; Leandersson, Karin ^LU

and Jirström, Karin ^LU

(2026) In Cancer Medicine 15(3).

Abstract

INTRODUCTION: The immune microenvironment plays a crucial role in the progression of colorectal cancer (CRC), but its variation across primary tumors and metastatic sites remains incompletely understood. In this study, we compared the composition and prognostic significance of the immune microenvironment in lung metastases, paired primary tumors, and liver metastases from a retrospective cohort of 216 patients with metastatic CRC who underwent pulmonary metastasectomy in a single Swedish institution.

METHODS: Immunohistochemistry was applied on tissue microarrays to evaluate CD3+, CD8+, CD20+, FoxP3+ immune cells, PD-L1+ immune cells and tumor cells, and tertiary lymphoid-like structures (TLLS).

RESULTS: Lung metastases... (More)

INTRODUCTION: The immune microenvironment plays a crucial role in the progression of colorectal cancer (CRC), but its variation across primary tumors and metastatic sites remains incompletely understood. In this study, we compared the composition and prognostic significance of the immune microenvironment in lung metastases, paired primary tumors, and liver metastases from a retrospective cohort of 216 patients with metastatic CRC who underwent pulmonary metastasectomy in a single Swedish institution.

METHODS: Immunohistochemistry was applied on tissue microarrays to evaluate CD3+, CD8+, CD20+, FoxP3+ immune cells, PD-L1+ immune cells and tumor cells, and tertiary lymphoid-like structures (TLLS).

RESULTS: Lung metastases exhibited significantly higher infiltration of all immune cell subsets compared to both primary tumors and liver metastases. FoxP3+ cell density was lower in liver metastases than in primary tumors. Immune cell infiltration in lung metastases was largely unaffected by neoadjuvant chemotherapy, except for lower FoxP3+ cell infiltration in treated cases. None of the immune markers bore prognostic significance in the overall analysis. However, high infiltration of FoxP3+, CD20+, and PD-L1+ immune cells, and presence of TLLSs in lung metastases were associated with improved overall survival in patients receiving adjuvant chemotherapy, with a significant prognostic treatment interaction. None of the immune markers were prognostic in primary tumors or liver metastases.

CONCLUSION: These findings underscore a distinct, more immunologically active immune microenvironment in CRC lung metastases compared to primary tumors and liver metastases, that suggestedly also predicts response to adjuvant chemotherapy. Immune profiling of lung metastases may thus pave the way for improved personalized treatment of these patients.

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Please use this url to cite or link to this publication: https://lup.lub.lu.se/record/3b78dfa0-e6f2-43cc-96c0-ec3e2cce6c35

author

Kuznyecov, Danyil ^LU ; Siesing, Christina ^LU ; Vidarsdottir, Halla ^LU ; Eberhard, Jakob ^LU ; Brunnström, Hans ^LU

; Leandersson, Karin ^LU

and Jirström, Karin ^LU

organization

publishing date

2026-03-20

type

Contribution to journal

publication status

published

subject

Cancer and Oncology

keywords

Humans, Colorectal Neoplasms/pathology, Lung Neoplasms/secondary, Female, Male, Lymphocytes, Tumor-Infiltrating/immunology, Chemotherapy, Adjuvant, Prognosis, Middle Aged, Tumor Microenvironment/immunology, Aged, Retrospective Studies, Liver Neoplasms/secondary, Adult, Biomarkers, Tumor, Aged, 80 and over, Forkhead Transcription Factors/metabolism

in

Cancer Medicine

volume

15

issue

3

article number

e71739

publisher

John Wiley & Sons Inc.

external identifiers

pmid:41858252

ISSN

2045-7634

DOI

10.1002/cam4.71739

language

English

LU publication?

yes

additional info

id

3b78dfa0-e6f2-43cc-96c0-ec3e2cce6c35

date added to LUP

2026-03-20 13:29:38

date last changed

2026-03-23 08:15:45

@article{3b78dfa0-e6f2-43cc-96c0-ec3e2cce6c35,
  abstract     = {{<p>INTRODUCTION: The immune microenvironment plays a crucial role in the progression of colorectal cancer (CRC), but its variation across primary tumors and metastatic sites remains incompletely understood. In this study, we compared the composition and prognostic significance of the immune microenvironment in lung metastases, paired primary tumors, and liver metastases from a retrospective cohort of 216 patients with metastatic CRC who underwent pulmonary metastasectomy in a single Swedish institution.</p><p>METHODS: Immunohistochemistry was applied on tissue microarrays to evaluate CD3+, CD8+, CD20+, FoxP3+ immune cells, PD-L1+ immune cells and tumor cells, and tertiary lymphoid-like structures (TLLS).</p><p>RESULTS: Lung metastases exhibited significantly higher infiltration of all immune cell subsets compared to both primary tumors and liver metastases. FoxP3+ cell density was lower in liver metastases than in primary tumors. Immune cell infiltration in lung metastases was largely unaffected by neoadjuvant chemotherapy, except for lower FoxP3+ cell infiltration in treated cases. None of the immune markers bore prognostic significance in the overall analysis. However, high infiltration of FoxP3+, CD20+, and PD-L1+ immune cells, and presence of TLLSs in lung metastases were associated with improved overall survival in patients receiving adjuvant chemotherapy, with a significant prognostic treatment interaction. None of the immune markers were prognostic in primary tumors or liver metastases.</p><p>CONCLUSION: These findings underscore a distinct, more immunologically active immune microenvironment in CRC lung metastases compared to primary tumors and liver metastases, that suggestedly also predicts response to adjuvant chemotherapy. Immune profiling of lung metastases may thus pave the way for improved personalized treatment of these patients.</p>}},
  author       = {{Kuznyecov, Danyil and Siesing, Christina and Vidarsdottir, Halla and Eberhard, Jakob and Brunnström, Hans and Leandersson, Karin and Jirström, Karin}},
  issn         = {{2045-7634}},
  keywords     = {{Humans; Colorectal Neoplasms/pathology; Lung Neoplasms/secondary; Female; Male; Lymphocytes, Tumor-Infiltrating/immunology; Chemotherapy, Adjuvant; Prognosis; Middle Aged; Tumor Microenvironment/immunology; Aged; Retrospective Studies; Liver Neoplasms/secondary; Adult; Biomarkers, Tumor; Aged, 80 and over; Forkhead Transcription Factors/metabolism}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{3}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Cancer Medicine}},
  title        = {{Tumor-Infiltrating Immune Cells Are More Abundant in Lung Metastases From Colorectal Cancer Than in Paired Primary Tumors and Their Prognostic Value Depends on Adjuvant Chemotherapy}},
  url          = {{http://dx.doi.org/10.1002/cam4.71739}},
  doi          = {{10.1002/cam4.71739}},
  volume       = {{15}},
  year         = {{2026}},
}

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Tumor-Infiltrating Immune Cells Are More Abundant in Lung Metastases From Colorectal Cancer Than in Paired Primary Tumors and Their Prognostic Value Depends on Adjuvant Chemotherapy