Organ-specific heterogeneity in tumor-infiltrating immune cells and cancer antigen expression in primary and autologous metastatic lung adenocarcinoma Journal Article
| Authors: | Restle, D.; Dux, J.; Li, X.; Byun, A. J.; Choe, J. K.; Li, Y.; Vaghjiani, R. G.; Thomas, C.; Misawa, K.; Tan, K. S.; Jones, D. R.; Chintala, N. K.; Adusumilli, P. S. |
| Article Title: | Organ-specific heterogeneity in tumor-infiltrating immune cells and cancer antigen expression in primary and autologous metastatic lung adenocarcinoma |
| Abstract: | Background: Tumor immune microenvironment (TIME) and cancer antigen expression, key factors for the development of immunotherapies, are usually based on the data from primary tumors due to availability of tissue for analysis; data from metastatic sites and their concordance with primary tumor are lacking. Although of the same origin from primary tumor, organ-specific differences in the TIME in metastases may contribute to discordant responses to immune checkpoint inhibitor agents. In immunologically 'cold' tumors, cancer antigen-targeted chimeric antigen receptor (CAR) T-cell therapy can promote tumor-infiltrating lymphocytes; however, data on distribution and intensity of cancer antigen expression in primary tumor and matched metastases are unavailable. Methods: We performed a retrospective review of a prospectively maintained database of patients who had undergone curative resection of pathological stage I-III primary lung adenocarcinoma from January 1995 to December 2012 followed by metastatic recurrence and resection of metastatic tumor (n=87). We investigated the relationship between the primary tumor and metastasis TIME (ie, tumor-infiltrating lymphocytes, tumor-associated macrophages, and programmed death-ligand 1 (PD-L1)) and cancer antigen expression (ie, mesothelin, CA125, and CEACAM6) using multiplex immunofluorescence. Results: Brain metastases (n=36) were observed to have fewer tumor-infiltrating lymphocytes and greater PD-L1-negative tumor-associated macrophages compared with the primary tumor (p<0.0001); this relatively inhibitory TIME was not observed in other metastatic sites. In one in three patients, expression of PD-L1 is discordant between primary and metastases. Effector-to-suppressor (E:S) cell ratio, median effector cells (CD20+ and CD3+) to suppressor cells (CD68/CD163+) ratio, in metastases was not significantly different between patients with varying E:S ratios in primary tumors. Cancer antigen distribution was comparable between primary and metastases; among patients with mesothelin, cancer antigen 125, or carcinoembryonic antigen adhesion molecule 6 expression in the primary tumor, the majority (51%-75%) had antigen expression in the metastases; however, antigen-expression intensity was heterogenous. Conclusions: In patients with lung adenocarcinoma, brain metastases, but not other sites of metastases, exhibited a relatively immune-suppressive TIME; this should be considered in the context of differential response to immunotherapy in brain metastases. Among patients with cancer antigen expression in the primary tumor, the majority had antigen expression in metastases; these data can inform the selection of antigen-targeted CARs to treat patients with metastatic lung adenocarcinoma. © 2023 Author(s) (or their employer(s)). |
| Keywords: | adult; human tissue; protein expression; aged; middle aged; cancer surgery; primary tumor; gene mutation; human cell; major clinical study; cancer recurrence; solid tumor; bone metastasis; cancer adjuvant therapy; cancer staging; brain tumor; brain neoplasms; lymph node metastasis; cd3 antigen; cd8 antigen; antigen expression; cd8+ t lymphocyte; tumor associated leukocyte; lymphocytes, tumor-infiltrating; metabolism; metastasis; image analysis; cell infiltration; lung neoplasms; epidermal growth factor receptor; myeloperoxidase; lung cancer; immunofluorescence; pathology; retrospective study; tumor antigen; biopsy; histology; cell heterogeneity; lung tumor; lung metastasis; cd20 antigen; lung adenocarcinoma; neutrophil; immunotherapy; antigens; cd4+ t lymphocyte; staining; brain metastasis; effector cell; cell count; cd4 antigen; tissue microarray; ca 125 antigen; macrophage; cd3+ t lymphocyte; k ras protein; software; kidney metastasis; immunocompetent cell; mesothelin; cd163 antigen; adrenal metastasis; cd68 antigen; soft tissue metastasis; programmed death 1 ligand 1; pleura metastasis; tumor microenvironment; adenocarcinoma of lung; tumor-associated macrophage; demographics; organ; wilcoxon signed ranks test; metastatic colon cancer; immune checkpoint inhibitor; never smoker; humans; human; male; female; article; programmed cell death 1 receptor; b7-h1 antigen; chimeric antigen receptor t-cell immunotherapy; current smoker; ex-smoker; receptors, chimeric antigen; carcinoembryonic antigen related cell adhesion molecule 6 |
| Journal Title: | Journal for ImmunoTherapy of Cancer |
| Volume: | 11 |
| Issue: | 6 |
| ISSN: | 2051-1426 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2023-06-01 |
| Start Page: | e006609 |
| Language: | English |
| DOI: | 10.1136/jitc-2022-006609 |
| PUBMED: | 37349126 |
| PROVIDER: | scopus |
| PMCID: | PMC10314697 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Prasad S Adusumilli -- Source: Scopus |
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