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Heterogeneous tumor-immune microenvironments between primary and metastatic carcinoid tumors differentially respond to anti-PD-L1 antibody therapy.

ABSTRACT: A pulmonary carcinoid tumor is a rare tumor that lacks a validated therapeutic approach for unresectable disease. Understanding the intersite tumor-immune heterogeneity is essential to harness the immune system for cancer therapy. However, little is known about the tumor-immune microenvironment (TIME). Here, we describe a patient who had heterogeneous TIME between primary and metastatic carcinoid tumors which differentially responded to chemoimmunotherapy. A 72-year-old man was diagnosed with an advanced pulmonary carcinoid tumor. CT-guided biopsies of lung and scapular tumors confirmed typical carcinoid (PD-L1, 1%-24%) and atypical carcinoid tumors (PD-L1, negative), respectively. Although the primary lung carcinoid tumor showed a partial response, the scapular tumor was significantly enlarged after two cycles of anti-PD-L1 antibody therapy in combination with carboplatin plus etoposide. We performed quantitative pathology imaging analysis with fluorescent multiplex immunohistochemistry. CD8⁺ T cell infiltration was detected in the PD-L1-positive primary lung tumor nest; however, it was mostly restrained in the stroma in a PD-L1-negative metastatic scapular tumor. Treg infiltrations into both tumor nests and stroma were detected in the lung tumor, which were not detected in the metastatic scapular tumor. This study provides the first evidence of coexistence of heterogeneous TIME within a single individual with a pulmonary carcinoid tumor. This study may provide new insights into the mechanism of primary resistance to chemoimmunotherapy in pulmonary carcinoid tumors.

SUBMITTER: Sakata S

PROVIDER: S-EPMC7862786 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Heterogeneous tumor-immune microenvironments between primary and metastatic carcinoid tumors differentially respond to anti-PD-L1 antibody therapy.

Sakata Shinya S Imamura Kosuke K Tajima Yuka Y Masuda Yuiko Y Sato Ryo R Yoshida Chieko C Okamoto Shinichiro S Saeki Sho S Tomita Yusuke Y Sakagami Takuro T

Thoracic cancer 20201209 3

A pulmonary carcinoid tumor is a rare tumor that lacks a validated therapeutic approach for unresectable disease. Understanding the intersite tumor-immune heterogeneity is essential to harness the immune system for cancer therapy. However, little is known about the tumor-immune microenvironment (TIME). Here, we describe a patient who had heterogeneous TIME between primary and metastatic carcinoid tumors which differentially responded to chemoimmunotherapy. A 72-year-old man was diagnosed with an ...[more]

PMID: 33300302

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Project description:Inflammatory myofibroblastic tumor is a rare mesenchymal tumor occurring at many anatomic sites, with a predilection for children and young adults. Often indolent, they can be locally aggressive and can metastasize, resulting in significant morbidity and mortality. Therapeutic options are often limited. The identification of underlying kinase mutations has allowed the use of targeted therapy in a subset of patients. Unfortunately, not all tumors harbor mutations and resistance to tyrosine kinase inhibitor therapy is a potential problem. We hypothesized that these tumors may be amenable to PD-L1 therapy given the immune nature of the tumor. PD-L1 expression in inflammatory myofibroblastic tumors has not yet been defined. The purpose of this study was to explore PD-L1 expression in inflammatory myofibroblastic tumors, as adaptive PD-L1 expression is known to enrich for response to anti-PD-1/PD-L1 therapies. Expression of PD-L1 (clone SP142) was assessed in 35 specimens from 28 patients. Positivity was defined as membranous expression in ≥5% of cells and evaluated separately in tumor and immune cells. Adaptive vs. constitutive patterns of tumor cell PD-L1 expression were assessed. PD-L1 status was correlated with clinicopathologic features. CD8+ T cell infiltrates were quantified by digital image analysis. ALK status was assessed by immunohistochemistry and/or FISH. Twenty-four (69%) tumors had PD-L1(+) tumor cells and 28 (80%) showed PD-L1(+) immune cells. Most recurrent and metastatic tumors (80%) and ALK(-) tumors (88%) were PD-L1(+). Adaptive PD-L1 expression was present in 23 (96%) of PD-L1(+) tumors, which also showed a three-four fold increase in CD8+ T cell infiltration relative to PD-L1(-) tumors. Constitutive PD-L1 expression was associated with larger tumor size (p = 0.002). Inflammatory myofibroblastic tumors show frequent constitutive and adaptive PD-L1 expression, the latter of which is thought to be predictive of response to anti-PD-1. These data support further investigation into PD-1/PD-L1 blockade in this tumor type.

Dataset Information

Heterogeneous tumor-immune microenvironments between primary and metastatic carcinoid tumors differentially respond to anti-PD-L1 antibody therapy.

Publications

Heterogeneous tumor-immune microenvironments between primary and metastatic carcinoid tumors differentially respond to anti-PD-L1 antibody therapy.

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