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The Tumor Microenvironment

The Tumor Microenvironment

Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...

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EML4-ALK Rearrangement Creates a Distinctive Myeloid Cell-Dominant Immunosuppressive Microenvironment in Lung Cancer.

Kosuke Arai^1,2, Yukari Nishito³, Hideaki Mizuno³

¹Department of Immune Medicine, National Cancer Center Research Institute, Tokyo, Japan.

Cancer Immunology Research

|July 8, 2025

Summary

Anaplastic lymphoma kinase (ALK) fusion-positive lung cancer develops a resistant tumor microenvironment. Targeting IL6R with immune checkpoint inhibitors shows promise for treating this resistant lung cancer.

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Experimental Metastasis and CTL Adoptive Transfer Immunotherapy Mouse Model

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Published on: November 26, 2010

Area of Science:

Oncology
Immunology
Genetics

Background:

Tyrosine kinase inhibitors (TKIs) are effective against anaplastic lymphoma kinase (ALK) fusion-positive lung adenocarcinoma but resistance develops.
Immune checkpoint inhibitors (ICIs) improve lung cancer prognosis, yet ALK+ lung adenocarcinoma shows limited response to immunotherapy, with unknown resistance mechanisms.

Purpose of the Study:

To investigate the tumor microenvironment (TME) in ALK+ lung adenocarcinoma and identify resistance mechanisms to immunotherapy.

Main Methods:

Analysis of tumor-infiltrating leukocytes and single-cell RNA sequencing in ALK+ and ALK- lung adenocarcinoma tissues.
Utilizing a murine ALK+ lung adenocarcinoma model to test IL6 receptor (IL6R) inhibitor and ICI combination therapy.

Main Results:

ALK+ lung adenocarcinoma exhibits a myeloid cell-dominant immunosuppressive TME with reduced effector T cells and increased myeloid-derived suppressor cells (MDSCs).
Inactivated macrophages expressing T cell-attractant chemokines and elevated MDSC-attractant chemokines (CXCL1, CXCL8) and IL6 were observed in ALK+ tumors.
IL6R inhibition reversed the immunosuppressive TME in a murine model, and combination therapy with ICI demonstrated significant antitumor effects.

Conclusions:

Fusion gene-mediated immunosuppressive TMEs contribute to immunotherapy resistance in ALK+ lung adenocarcinoma.
Targeting IL6R in combination with ICIs offers a novel therapeutic strategy for ALK+ lung adenocarcinoma.