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Elfving, H., Thurfjell, V., Mattsson, J. S., Backman, M., Strell, C. & Micke, P. (2024). Tumor Heterogeneity Confounds Lymphocyte Metrics in Diagnostic Lung Cancer Biopsies. Archives of Pathology & Laboratory Medicine, 148(1), e18-e24
Open this publication in new window or tab >>Tumor Heterogeneity Confounds Lymphocyte Metrics in Diagnostic Lung Cancer Biopsies
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2024 (English)In: Archives of Pathology & Laboratory Medicine, ISSN 0003-9985, E-ISSN 1543-2165, Vol. 148, no 1, p. e18-e24Article in journal (Refereed) Published
Abstract [en]

Context.—The immune microenvironment is involved in fundamental aspects of tumorigenesis, and immune scores are now being developed for clinical diagnostics. Objective.—To evaluate how well small diagnostic biopsies and tissue microarrays (TMAs) reflect immune cell infiltration compared to the whole tumor slide, in tissue from patients with non–small cell lung cancer. Design.—A TMA was constructed comprising tissue from surgical resection specimens of 58 patients with non–small cell lung cancer, with available preoperative biopsy material. Whole sections, biopsies, and TMA were stained for the pan-T lymphocyte marker CD3 to determine densities of tumor-infiltrating lymphocytes. Immune cell infiltration was assessed semiquantitatively as well as objectively with a microscopic grid count. For 19 of the cases, RNA sequencing data were available. Results.—The semiquantitative comparison of immune cell infiltration between the whole section and the biopsy displayed fair agreement (intraclass correlation coefficient [ICC], 0.29; P ¼ .01; CI, 0.03–0.51). In contrast, the TMA showed substantial agreement compared with the whole slide (ICC, 0.64; P , .001; CI, 0.39–0.79). The grid-based method did not enhance the agreement between the different tissue materials. The comparison of CD3 RNA sequencing data with CD3 cell annotations confirmed the poor representativity of biopsies as well as the stronger correlation for the TMA cores. Conclusions.—Although overall lymphocyte infiltration is relatively well represented on TMAs, the representativity in diagnostic lung cancer biopsies is poor. This finding challenges the concept of using biopsies to establish immune scores as prognostic or predictive biomarkers for diagnostic applications.

Place, publisher, year, edition, pages
Archives of Pathology and Laboratory Medicine, 2024
Keywords
lung cancer, immunotherapy, checkpoint inhibitors, tumor microenvironment, prognosis, PD-L1, lymphocytes
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-517148 (URN)10.5858/arpa.2022-0327-oa (DOI)001137617500012 ()
Available from: 2023-12-04 Created: 2023-12-04 Last updated: 2024-02-21Bibliographically approved
Mezheyeuski, A., Backman, M., Mattsson, J. S., Martin-Bernabe, A., Larsson, C., Hrynchyk, I., . . . Sjöblom, T. (2023). An immune score reflecting pro- and anti-tumoural balance of tumour microenvironment has major prognostic impact and predicts immunotherapy response in solid cancers. EBioMedicine, 88, Article ID 104452.
Open this publication in new window or tab >>An immune score reflecting pro- and anti-tumoural balance of tumour microenvironment has major prognostic impact and predicts immunotherapy response in solid cancers
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2023 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 88, article id 104452Article in journal (Refereed) Published
Abstract [en]

Background: Cancer immunity is based on the interaction of a multitude of cells in the spatial context of the tumour tissue. Clinically relevant immune signatures are therefore anticipated to fundamentally improve the accuracy in predicting disease progression.

Methods: Through a multiplex in situ analysis we evaluated 15 immune cell classes in 1481 tumour samples. Single-cell and bulk RNAseq data sets were used for functional analysis and validation of prognostic and predictive associations.

Findings: By combining the prognostic information of anti-tumoural CD8+ lymphocytes and tumour supportive CD68+CD163+ macrophages in colorectal cancer we generated a signature of immune activation (SIA). The prognostic impact of SIA was independent of conventional parameters and comparable with the state-of-art immune score. The SIA was also associated with patient survival in oesophageal adenocarcinoma, bladder cancer, lung adenocarcinoma and melanoma, but not in endometrial, ovarian and squamous cell lung carcinoma. We identified CD68+CD163+ macrophages as the major producers of complement C1q, which could serve as a surrogate marker of this macrophage subset. Consequently, the RNA-based version of SIA (ratio of CD8A to C1QA) was predictive for survival in independent RNAseq data sets from these six cancer types. Finally, the CD8A/C1QA mRNA ratio was also predictive for the response to checkpoint inhibitor therapy.

Interpretation: Our findings extend current concepts to procure prognostic information from the tumour immune microenvironment and provide an immune activation signature with high clinical potential in common human cancer types.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Tumour immunology, Macrophages, Immunoscore
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-501100 (URN)10.1016/j.ebiom.2023.104452 (DOI)000963637000001 ()36724681 (PubMedID)
Funder
Swedish Cancer Society, CAN 2018/772Swedish Cancer Society, CAN 2019/447Swedish Cancer Society, CAN 2018/816Region UppsalaInsamlingsstiftelsen Lions Cancerforskningsfond Mellansverige Uppsala-ÖrebroErik, Karin och Gösta Selanders FoundationP.O. Zetterling Foundation
Available from: 2023-05-03 Created: 2023-05-03 Last updated: 2023-05-03Bibliographically approved
Hikmet Noraddin, F., Rassy, M., Backman, M., Méar, L., Mattsson, J. S., Djureinovic, D., . . . Lindskog, C. (2023). Expression of cancer-testis antigens in the immune microenvironment of non-small cell lung cancer. Molecular Oncology, 17(12), 2603-2617
Open this publication in new window or tab >>Expression of cancer-testis antigens in the immune microenvironment of non-small cell lung cancer
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2023 (English)In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 17, no 12, p. 2603-2617Article in journal (Refereed) Published
Abstract [en]

The antigenic repertoire of tumors is critical for successful anti-cancer immune response and the efficacy of immunotherapy. Cancer-testis antigens (CTAs) are targets of humoral and cellular immune reactions. We aimed to characterize CTA expression in non-small cell lung cancer (NSCLC) in the context of the immune microenvironment. Of 90 CTAs validated by RNA sequencing, eight CTAs (DPEP3, EZHIP, MAGEA4, MAGEB2, MAGEC2, PAGE1, PRAME, and TKTL1) were selected for immunohistochemical profiling in cancer tissues from 328 NSCLC patients. CTA expression was compared with immune cell densities in the tumor environment and with genomic, transcriptomic, and clinical data. Most NSCLC cases (79%) expressed at least one of the analyzed CTAs, and CTA protein expression correlated generally with RNA expression. CTA profiles were associated with immune profiles: high MAGEA4 expression was related to M2 macrophages (CD163) and regulatory T cells (FOXP3), low MAGEA4 was associated with T cells (CD3), and high EZHIP was associated with plasma cell infiltration (adj. P-value < 0.05). None of the CTAs correlated with clinical outcomes. The current study provides a comprehensive evaluation of CTAs and suggests that their association with immune cells may indicate in situ immunogenic effects. The findings support the rationale to harness CTAs as targets for immunotherapy.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
cancer-testis antigens, immune phenotype, immune-oncology, non-small cell lung cancer
National Category
Cancer and Oncology Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-522496 (URN)10.1002/1878-0261.13474 (DOI)001020469000001 ()37341056 (PubMedID)
Funder
Swedish Cancer Society, 21 1790Knut and Alice Wallenberg Foundation, 2015.0344Sjöberg Foundation
Available from: 2024-02-07 Created: 2024-02-07 Last updated: 2024-02-07Bibliographically approved
Pellinen, T., Paavolainen, L., Martín-Bernabé, A., Papatella Araujo, R., Strell, C., Mezheyeuski, A., . . . Östman, A. (2023). Fibroblast subsets in non-small cell lung cancer: Associations with survival, mutations, and immune features. Journal of the National Cancer Institute, 115(1), 71-82
Open this publication in new window or tab >>Fibroblast subsets in non-small cell lung cancer: Associations with survival, mutations, and immune features
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2023 (English)In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 115, no 1, p. 71-82Article in journal (Refereed) Published
Abstract [en]

Background

Cancer-associated fibroblasts (CAFs) are molecularly heterogeneous mesenchymal cells that interact with malignant cells and immune cells and confer anti- and protumorigenic functions. Prior in situ profiling studies of human CAFs have largely relied on scoring single markers, thus presenting a limited view of their molecular complexity. Our objective was to study the complex spatial tumor microenvironment of non-small cell lung cancer (NSCLC) with multiple CAF biomarkers, identify novel CAF subsets, and explore their associations with patient outcome.

Methods

Multiplex fluorescence immunohistochemistry was employed to spatially profile the CAF landscape in 2 population-based NSCLC cohorts (n = 636) using antibodies against 4 fibroblast markers: platelet-derived growth factor receptor-alpha (PDGFRA) and -beta (PDGFRB), fibroblast activation protein (FAP), and alpha-smooth muscle actin (αSMA). The CAF subsets were analyzed for their correlations with mutations, immune characteristics, and clinical variables as well as overall survival.

Results

Two CAF subsets, CAF7 (PDGFRA-/PDGFRB+/FAP+/αSMA+) and CAF13 (PDGFRA+/PDGFRB+/FAP-/αSMA+), showed statistically significant but opposite associations with tumor histology, driver mutations (tumor protein p53 [TP53] and epidermal growth factor receptor [EGFR]), immune features (programmed death-ligand 1 and CD163), and prognosis. In patients with early stage tumors (pathological tumor-node-metastasis IA-IB), CAF7 and CAF13 acted as independent prognostic factors.

Conclusions

Multimarker-defined CAF subsets were identified through high-content spatial profiling. The robust associations of CAFs with driver mutations, immune features, and outcome suggest CAFs as essential factors in NSCLC progression and warrant further studies to explore their potential as biomarkers or therapeutic targets. This study also highlights multiplex fluorescence immunohistochemistry–based CAF profiling as a powerful tool for the discovery of clinically relevant CAF subsets.

Place, publisher, year, edition, pages
Oxford University Press, 2023
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-492026 (URN)10.1093/jnci/djac178 (DOI)000867162300001 ()36083003 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilInsamlingsstiftelsen Lions Cancerforskningsfond Mellansverige Uppsala-ÖrebroSjöberg Foundation
Available from: 2022-12-30 Created: 2022-12-30 Last updated: 2023-04-18Bibliographically approved
Backman, M., Strell, C., Lindberg, A., Mattsson, J. S. M., Elfving, H., Brunnström, H., . . . Micke, P. (2023). Spatial immunophenotyping of the tumour microenvironment in non-small cell lung cancer. European Journal of Cancer, 185, 40-52
Open this publication in new window or tab >>Spatial immunophenotyping of the tumour microenvironment in non-small cell lung cancer
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2023 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 185, p. 40-52Article in journal (Refereed) Published
Abstract [en]

Introduction: Immune cells in the tumour microenvironment are associated with prognosis and response to therapy. We aimed to comprehensively characterise the spatial im-mune phenotypes in the mutational and clinicopathological background of non-small cell lung cancer (NSCLC).

Methods: We established a multiplexed fluorescence imaging pipeline to spatially quantify 13 immune cell subsets in 359 NSCLC cases: CD4 effector cells (CD4-Eff), CD4 regulatory cells (CD4-Treg), CD8 effector cells (CD8-Eff), CD8 regulatory cells (CD8-Treg), B-cells, natural killer cells, natural killer T-cells, M1 macrophages (M1), CD163 thorn myeloid cells (CD163), M2 macrophages (M2), immature dendritic cells (iDCs), mature dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs).

Results: CD4-Eff cells, CD8-Eff cells and M1 macrophages were the most abundant immune cells invading the tumour cell compartment and indicated a patient group with a favourable prognosis in the cluster analysis. Likewise, single densities of lymphocytic subsets (CD4-Eff, CD4-Treg, CD8-Treg, B-cells and pDCs) were independently associated with longer survival. However, when these immune cells were located close to CD8-Treg cells, the favourable impact was attenuated. In the multivariable Cox regression model, including cell densities and distances, the densities of M1 and CD163 cells and distances between cells (CD8-Treg-B-cells, CD8-Eff-cancer cells and B-cells-CD4-Treg) demonstrated positive prognostic impact, whereas short M2-M1 distances were prognostically unfavourable.

Conclusion: We present a unique spatial profile of the in situ immune cell landscape in NSCLC as a publicly available data set. Cell densities and cell distances contribute independently to prognostic information on clinical outcomes, suggesting that spatial information is crucial for diagnostic use.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Immune cell infiltration, Multiplex imaging, Checkpoint therapy, Tumour microenvironment, Lung cancer, NSCLC
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-502648 (URN)10.1016/j.ejca.2023.02.012 (DOI)000959970600001 ()36963351 (PubMedID)
Funder
Swedish Cancer SocietySjöberg FoundationInsamlingsstiftelsen Lions Cancerforskningsfond Mellansverige Uppsala-ÖrebroErik, Karin och Gösta Selanders Foundation
Note

De två sista författarna delar sistaförfattarskapet

Available from: 2023-05-31 Created: 2023-05-31 Last updated: 2024-03-06Bibliographically approved
Elfving, H., Broström, E., Moens, L. N. .., Almlöf, J., Cerjan, D., Lauter, G., . . . Micke, P. (2021). Evaluation of NTRK immunohistochemistry as a screening method for NTRK gene fusion detection in non-small cell lung cancer. Lung Cancer, 151, 53-59
Open this publication in new window or tab >>Evaluation of NTRK immunohistochemistry as a screening method for NTRK gene fusion detection in non-small cell lung cancer
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2021 (English)In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 151, p. 53-59Article in journal (Refereed) Published
Abstract [en]

Purpose: The small molecule inhibitors larotrectinib and entrectinib have recently been approved as cancer agnostic drugs in patients with tumours harbouring a rearrangement of the neurotrophic tropomyosin receptor kinase (NTRK). These oncogenic fusions are estimated to occur in 0.1-3 % of non-small cell lung cancers (NSCLC). Although molecular techniques are most reliable for fusion detection, immunohistochemical analysis is considered valuable for screening. Therefore, we evaluated the newly introduced diagnostic immunohistochemical assay (clone EPR17341) on a representative NSCLC cohort.

Methods: Cancer tissue from 688 clinically and molecularly extensively annotated NSCLC patients were comprised on tissue microarrays and stained with the pan-TRK antibody clone EPR17341. Positive cases were further analysed with the TruSight Tumor 170 RNA assay (Illumina). Selected cases were also tested with a NanoString NTRK fusion assay. For 199 cases, NTRK RNA expression data were available from previous RNA sequencing analysis.

Results: Altogether, staining patterns for 617 NSCLC cases were evaluable. Of these, four cases (0.6 %) demonstrated a strong diffuse cytoplasmic and membranous staining, and seven cases a moderate staining (1.1 %). NanoString or TST170-analysis could not confirm an NTRK fusion in any of the IHC positive cases, or any of the cases with high mRNA levels. In the four cases with strong staining intensity in the tissue microarray, whole section staining revealed marked heterogeneity of NTRK protein expression.

Conclusion: The presence of NTRK fusion genes in non-small cell lung cancer is exceedingly rare. The use of the immunohistochemical NTRK assay will result in a small number of false positive cases. This should be considered when the assay is applied as a screening tool in clinical diagnostics.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
Diagnostics, Entrectinib, Gene fusion, Larotrectinib, Lung adenocarcinoma, NTRK
National Category
Clinical Laboratory Medicine Cancer and Oncology
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-431535 (URN)10.1016/j.lungcan.2020.11.023 (DOI)000608584100010 ()33310622 (PubMedID)
Funder
Swedish Cancer SocietyErik, Karin och Gösta Selanders FoundationInsamlingsstiftelsen Lions Cancerforskningsfond Mellansverige Uppsala-Örebro
Note

De två första författarna delar förstaförfattarskapet

Available from: 2021-01-14 Created: 2021-01-14 Last updated: 2024-01-15Bibliographically approved
Bogatyrova, O., Mattsson, J. S., Ross, E. M., Sanderson, M. P., Backman, M., Botling, J., . . . Micke, P. (2021). FGFR1 overexpression in non-small cell lung cancer is mediated by genetic and epigenetic mechanisms and is a determinant of FGFR1 inhibitor response. European Journal of Cancer, 151, 136-149
Open this publication in new window or tab >>FGFR1 overexpression in non-small cell lung cancer is mediated by genetic and epigenetic mechanisms and is a determinant of FGFR1 inhibitor response
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2021 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 151, p. 136-149Article in journal (Refereed) Published
Abstract [en]

Amplification of fibroblast growth factor receptor 1 (FGFR1) in non-small cell lung cancer (NSCLC) has been considered as an actionable drug target. However, pan-FGFR tyrosine kinase inhibitors did not demonstrate convincing clinical efficacy in FGFR1-amplified NSCLC patients. This study aimed to characterise the molecular context of FGFR1 expression and to define biomarkers predictive of FGFR1 inhibitor response.

In this study, 635 NSCLC samples were characterised for FGFR1 protein expression by immunohistochemistry and copy number gain (CNG) by in situ hybridisation (n = 298) or DNA microarray (n = 189). FGFR1 gene expression (n = 369) and immune cell profiles (n = 309) were also examined. Furthermore, gene expression, methylation and microRNA data from The Cancer Genome Atlas (TCGA) were compared. A panel of FGFR1-amplified NSCLC patient-derived xenograft (PDX) models were tested for response to the selective FGFR1 antagonist M6123.

A minority of patients demonstrated FGFR1 CNG (10.5%) or increased FGFR1 mRNA (8.7%) and protein expression (4.4%). FGFR1 CNG correlated weakly with FGFR1 gene and protein expression. Tumours overexpressing FGFR1 protein were typically devoid of driver alterations (e.g. EGFR, KRAS) and showed reduced infiltration of T-lymphocytes and lower PD-L1 expression. Promoter methylation and microRNA were identified as regulators of FGFR1 expression in NSCLC and other cancers. Finally, NSCLC PDX models demonstrating FGFR1 amplification and FGFR1 protein overexpression were sensitive to M6123.

The unique molecular and immune features of tumours with high FGFR1 expression provide a rationale to stratify patients in future clinical trials of FGFR1 pathway-targeting agents.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
FGFR1, Non-small cell lung cancer, Promoter methylation, miRNA, Cancer immunity
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology; Pathology
Identifiers
urn:nbn:se:uu:diva-448907 (URN)10.1016/j.ejca.2021.04.005 (DOI)000660301100014 ()33984662 (PubMedID)
Funder
Swedish Cancer SocietyErik, Karin och Gösta Selanders Foundation
Note

De tre första författarna delar förstaförfattarskapet

De två sista författarna delar sistaförfattarskapet

Available from: 2021-07-13 Created: 2021-07-13 Last updated: 2024-01-15Bibliographically approved
Backman, M., La Fleur, L., Kurppa, P., Djureinovic, D., Elfving, H., Brunnström, H., . . . Micke, P. (2021). Infiltration of NK and plasma cells is associated with a distinct immune subset in non‐small cell lung cancer. Journal of Pathology, 255(3), 243-256
Open this publication in new window or tab >>Infiltration of NK and plasma cells is associated with a distinct immune subset in non‐small cell lung cancer
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2021 (English)In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 255, no 3, p. 243-256Article in journal (Refereed) Published
Abstract [en]

Immune cells of the tumor microenvironment are central but erratic targets for immunotherapy. The aim of this study was to characterize novel patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to its molecular and clinicopathologic characteristics. Lymphocytes (CD3+, CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+), PD1+, and PD-L1+ were annotated on a tissue microarray including 357 NSCLC cases. Somatic mutations were analyzed by targeted sequencing for 82 genes and a tumor mutational load score was estimated. Transcriptomic immune patterns were established in 197 patients based on RNA sequencing data. The immune cell infiltration was variable and showed only poor association with specific mutations. The previously defined immune phenotypic patterns, desert, inflamed, and immune excluded, comprised 30, 13, and 57% of cases, respectively. Notably, mRNA immune activation and high estimated tumor mutational load were unique only for the inflamed pattern. However, in the unsupervised cluster analysis, including all immune cell markers, these conceptual patterns were only weakly reproduced. Instead, four immune classes were identified: (1) high immune cell infiltration, (2) high immune cell infiltration with abundance of CD20+ B cells, (3) low immune cell infiltration, and (4) a phenotype with an imprint of plasma cells and NK cells. This latter class was linked to better survival despite exhibiting low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, CTLA4). This compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC reveals two previously unrecognized immune classes. A refined immune classification, including traits of the humoral and innate immune response, is important to define the immunogenic potency of NSCLC in the era of immunotherapy. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Place, publisher, year, edition, pages
John Wiley & SonsWiley, 2021
Keywords
immune cell infiltration, PD-L1, checkpoint therapy, tumor microenvironment, lung cancer, NSCLC, p53
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-465008 (URN)10.1002/path.5772 (DOI)000688429600001 ()34339045 (PubMedID)
Funder
Swedish Cancer SocietySjöberg FoundationEU, European Research Council
Available from: 2022-01-17 Created: 2022-01-17 Last updated: 2024-01-15Bibliographically approved
Goldmann, T., Marwitz, S., Nitschkowski, D., Krupar, R., Backman, M., Elfving, H., . . . Strell, C. (2021). PD-L1 amplification is associated with an immune cell rich phenotype in squamous cell cancer of the lung. Cancer Immunology and Immunotherapy, 70(9), 2577-2587
Open this publication in new window or tab >>PD-L1 amplification is associated with an immune cell rich phenotype in squamous cell cancer of the lung
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2021 (English)In: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 70, no 9, p. 2577-2587Article in journal (Refereed) Published
Abstract [en]

Gene amplification is considered to be one responsible cause for upregulation of Programmed Death Ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) and to represent a specific molecular subgroup possibly associated with immunotherapy response. Our aim was to analyze the frequency of PD-L1 amplification, its relation to PD-L1 mRNA and protein expression, and to characterize the immune microenvironment of amplified cases. The study was based on two independent NSCLC cohorts, including 354 and 349 cases, respectively. Tissue microarrays were used to evaluate PD-L1 amplification by FISH and PD-L1 protein by immunohistochemistry. Immune infiltrates were characterized immunohistochemically by a panel of immune markers (CD3, CD4, CD8, PD-1, Foxp3, CD20, CD138, CD168, CD45RO, NKp46). Mutational status was determined by targeted sequencing. RNAseq data was available for 197 patients. PD-L1 amplification was detected in 4.5% of all evaluable cases. PD-L1 amplification correlated only weakly with mRNA and protein expression. About 37% of amplified cases were negative for PD-L1 protein. PD-L1 amplification did not show any association with the mutational status. In squamous cell cancer, PD-L1 amplified cases were enriched among patients with high tumoral immune cell infiltration and showed gene expression profiles related to immune exhaustion. In conclusion, PD-L1 amplification correlates with PD-L1 expression in squamous cell cancer and was associated with an immune cell rich tumor phenotype. The correlative findings help to understand the role of PD-L1 amplification as an important immune escape mechanism in NSCLC and suggest the need to further evaluate PD-L1 amplification as predictive biomarker for checkpoint inhibitor therapy.

Place, publisher, year, edition, pages
Springer NatureSpringer Nature, 2021
Keywords
Check-point inhibitors, Lung cancer, Microenvironment, Immunotherapy, PD-L1 amplification
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-454352 (URN)10.1007/s00262-020-02825-z (DOI)000617413800003 ()33576873 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2021-09-28 Created: 2021-09-28 Last updated: 2024-01-15Bibliographically approved
Moreno-Ruiz, P., Corvigno, S., te Grootenhuis, N. C., La Fleur, L., Backman, M., Strell, C., . . . Östman, A. (2021). Stromal FAP is an independent poor prognosis marker in non-small cell lung adenocarcinoma and associated with p53 mutation. Lung Cancer, 155, 10-19
Open this publication in new window or tab >>Stromal FAP is an independent poor prognosis marker in non-small cell lung adenocarcinoma and associated with p53 mutation
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2021 (English)In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 155, p. 10-19Article in journal (Refereed) Published
Abstract [en]

Objectives

Fibroblasts regulate tumor growth and immune surveillance. Here, we study FAP, PDGFβR and α-SMA fibroblast markers in a well-annotated clinical cohort of non–small-cell lung cancer (NSCLC) for analyses of associations with immune cell infiltration, mutation status and survival.

Materials and Methods

A well-annotated NSCLC cohort was subjected to IHC analyses of stromal expression of FAP, PDGFβR and α-SMA and of stromal CD8 density. Fibroblast markers-related measurements were analyzed with regard to potential associations with CD8 density, cancer genetic driver mutations, survival and PD-L1 expression in the whole NSCLC cohort and in subsets of patients.

Results

High stromal FAP expression was identified as an independent poor prognostic marker in the whole study population (HR 1.481; 95 % CI, 1.012–2.167, p = 0.023) and in the histological subset of adenocarcinoma (HR 1.720; 95 % CI, 1.126–2.627, p = 0.012). Among patients with adenocarcinoma, a particularly strong association of FAP with poor survival was detected in patients with low stromal CD8 infiltration, and in other subpopulations identified by specific clinical characteristics; elderly patients, females, non-smokers and patients with normal ECOG performance status. α-SMA expression was negatively associated with CD8 infiltration in non-smokers, but none of the fibroblast markers expression was associated with CD8 density in the whole study population. Significant associations were detected between presence of p53 mutations and high α-SMA (p = 0.003) and FAP expression (p < 0.001).

Conclusion

The study identifies FAP intensity as a candidate independent NSCLC prognostic biomarker. The study also suggests continued analyses of the relationships between genetic driver mutations and the composition of tumor stroma, as well as continued probing of marker-defined fibroblasts as NSCLC subset-specific modifiers of immune surveillance and outcome.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
FAP, Fibroblast, Stroma, PDGFβR, α-SMA, Biomarkers, CD8, Non-small-cell lung cancer
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-443971 (URN)10.1016/j.lungcan.2021.02.028 (DOI)000644431300002 ()33706022 (PubMedID)
Funder
Swedish Cancer Society, CAN 2015/707Swedish Cancer Society, CAN 2018/831Knut and Alice Wallenberg Foundation, KAW 2015.0063
Note

De två första författarna delar förstaförfattarskapet

Available from: 2021-06-09 Created: 2021-06-09 Last updated: 2024-01-15Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-8804-1012

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